Treating urinary incontinence using prodrugs of GABA analogs

ABSTRACT

Disclosed herein are methods of using prodrugs of GABA analogs and pharmaceutical compositions thereof to treat and/or prevent urinary incontinence in humans, and pharmaceutical compositions of prodrugs of GABA analogs useful in treating and/or preventing urinary incontinence.

This application claims priority under 35 U.S.C. §119 (e) from U.S.Provisional Application Ser. Nos. 60/502,585, 60/505,210, 60/512,288 and60/538,748, filed on Sep. 11, 2003, Sep. 22, 2003, Oct. 17, 2003 andJan. 22, 2004.

1. TECHNICAL FIELD

The methods and compositions disclosed herein relate generally totreating urinary incontinence in a patient. More specifically, disclosedherein are methods of using prodrugs of GABA analogs and pharmaceuticalcompositions thereof to treat and/or prevent urinary incontinence inpatients.

2. BACKGROUND

According to the American Foundation for Urologic Disease, over 17million Americans suffer from overactive bladder. Incontinence isparticularly common in the elderly and is present in approximately fiftypercent of nursing home patients. Further, urinary incontinence affectsnearly all women in some form during their lifetime and is ofsignificant medical and social concern to those who experience theaffliction.

Urinary incontinence arises from the anatomy and the physiology of theurinary tract, which is composed of a bladder and a sphincter.Anatomically, the bladder consists of the bladder musculature known asdetrusor and the trigone. The sphincter includes the bladder neck andthe proximal urethra. The detrusor muscle is innervated by the pelvicnerve through the parasympathetic nervous system, and the bladder neckand proximal urethra are innervated by the sympathetic nervous system(See, “Chapter 215-Urinary Incontinence,” The Merck Manual, 17^(th) Ed.,M. H. Beers and R. Berkow, eds., Merck Research Laboratories, WhitehouseStation, N.J., 1999, pp. 1816-1824).

The major functions of the bladder are the storage and expulsion ofurine. The bladder is responsible for accommodating increasing volumesof urine at low pressures. Normally, the bladder remains closed duringbladder filling and continence is maintained as long as the bladder neckand urethral pressure exceeds intravesical pressure. Voluntary voidingoccurs when intravesical pressure exceeds bladder neck and urethralpressure, and involuntary voiding, also known as involuntaryincontinence, occurs when the travesical pressure exceeds the bladderneck and urethral pressure. Involuntary incontinence, also known as urgeincontinence and overactive bladder, occurs with a loss of a largevolume of urine accompanied by symptoms of urgency, frequency andnocturia caused by an unstable bladder or detrusor instability. Thepatient may lose urine with a change in position or with auditorystimulation. The loss of small volumes of urine usually occurs becauseof bladder over-distension by a large amount of residual urine; thiscondition is referred to as overflow incontinence. Urinary incontinenceis also known as overactive bladder, which exhibits symptoms of urinaryfrequency or urge incontinence.

Incontinence can be caused by a variety of factors including pregnancy,estrogen deficiency, general weakening of the sphincter or pelvic floormuscles, surgery along the urinary tract, infection and other maladieslocalized in the urinary tract. Several types of incontinence includingstress incontinence, urge incontinence, and total incontinence exist.Stress incontinence occurs under physical stress and individualssuffering from this type of incontinence might experience symptomsresulting in urine discharge during physically stressful events.Examples of stressful events include coughing, laughing, sneezing, andrigorous exercise. Symptoms of urge incontinence are characterized by anurgent desire to urinate and can result in total discharge of thebladder. This type of incontinence can occur at any time, but frequentlyoccurs when a person has a sudden change in their physical position.Total incontinence is characterized by a total lack of control overurine discharge and is frequently caused by a complete failure of thesphincter muscles.

Urinary incontinence is an unwanted side effect associated withadministration of a number of therapeutic drugs such as diuretics (e.g.,furosemide and bumetamide), anticholinergics (e.g., antihistamines andbenztropine), psychoactive drugs such as tricyclic antidepressants,antipsychotics, opioids, calcium-channel blockers, vincristine and ACEinhibitors (e.g., captopril) (Merck Manual, ibid., p. 1816).

Current treatments for incontinence include protective underwear such asdiapers or a urinary catheter that collects discharged urine. Thesetypes of treatments can be uncomfortable, unsightly, and sociallyawkward. Pelvic exercises are also used to strengthen weak pelvicmuscles. However, such exercises have limited affect, especially if theperson does not perform the exercises properly or on a regular basis.Additionally, surgery is often performed to tighten the sphinctermuscles. Surgery is a rather severe, and possibly dangerous, treatmentand is typically performed as a last resort if all other treatmentsfail.

Drug therapy is an alternative treatment for incontinence. The type ofdrug that is used can vary depending on the type and cause ofincontinence. For example, menopausal and post-menopausal women oftenexperience estrogen deficiency, which causes a variety of symptomsincluding a thinning of the urethral and vaginal mucosa. Thinning of theurethral mucosa can result in a lack of urethral pressure and thusinduce stress incontinence. Estrogen replacement therapy may helpcontrol menopause-related incontinence because some of the estrogen willreach and stimulate estrogen receptors in the urethral wall. Stimulationof estrogen receptors triggers an increase in the thickness of theurethral mucosa, which increases urethral pressure and helps to controlincontinence (Merkerj, So. Medical J. 2001 (94:10) 952-957).

In practice, estrogen is administered vaginally, orally, ortransdermally. These forms of administration can cause serious sideeffects because normal and healthy tissue outside the urinary tract,which is the desired treatment area, are exposed to estrogen. Examplesof possible side effects include breast tenderness, vaginal bleeding,cancer such as endometrial carcinoma, susceptibility to hypertension andrisk of abnormal blood clotting. The risk of side effects is evengreater if sustained use of estrogen occurs over a prolonged period.Therefore, estrogen administration may be unwarranted if the main goalof therapy is to treat incontinence.

Other agents that increase the tone of the internal and externalsphincter muscles may be used to treat incontinence. Examples of theseagents include sympathomimetics such as α-adrenergic agonists andnicotinic cholinergic agonists. However, current methods of deliveringthese agents have problems similar to the method for deliveringestrogen. Areas outside the urinary tract are exposed to the agent,which increases the risk of side effects. For example, sympathomimeticscan result in elevated blood pressure, stimulation of the centralnervous system resulting in insomnia and anxiety, dizziness, tremors,and cardiac arrhythmias. Nicotinic cholinergic agonists can also haveharmful effects because there are nicotinic cholinergic receptors in theskeletal muscles, autonomic ganglia and the adrenal medulla. Thus,treatment using nicotinic cholinergic agonists can also cause a varietyof side effects.

The γ-aminobutyric acid (γ-aminobutyric acid is abbreviated herein as“GABA”) analog gabapentin (1) has been approved in the United States forthe treatment of epileptic seizures and post-herpetic neuralgia. Thedrug has also shown efficacy in controlled studies for treatingneuropathic pain of varying etiologies. Gabapentin has been used totreat a number of other medical disorders (Magnus, Epilepsia 1999, 40,S66-72).

The broad pharmaceutical activities of GABA analogs such as gabapentinhas stimulated intensive interest in preparing related compounds thathave superior pharmaceutical properties in comparison to GABA, e.g., theability to cross the blood brain barrier (see, e.g., Satzinger et al.,U.S. Pat. No. 4,024,175; Silverman et al., U.S. Pat. No. 5,563,175;Horwell et al., U.S. Pat. No. 6,020,370; Silverman et al., U.S. Pat. No.6,028,214; Horwell et al., U.S. Pat. No. 6,103,932; Silverman et al.,U.S. Pat. No. 6,117,906; Silverman, International Publication No. WO92/09560; Silverman et al., International Publication No. WO 93/23383;Horwell et al., International Publication No. WO 97/29101, Horwell etal., International Publication No. WO 97/33858; Horwell et al.,International Publication No. WO 97/33859; Bryans et al., InternationalPublication No. WO 98/17627; Guglietta et al., International PublicationNo. WO 99/08671; Bryans et al., International Publication No. WO99/21824; Bryans et al., International Publication No. WO 99/31057;Belliotti et al., International Publication No. WO 99/31074; Bryans etal., International Publication No. WO 99/31075; Bryans et al.,International Publication No. WO 99/61424; Bryans et al., InternationalPublication No. WO 00/15611; Bellioti et al., International PublicationNo. WO 00/31020; Bryans et al., International Publication No. WO00/50027; and Bryans et al., International Publication No. WO 02/00209).One analog of particular interest is pregabalin (2), which may possessgreater potency in pre-clinical models of pain and epilepsy thangabapentin. GABA analogs such as gabapentin and pregabalin have beenused to treat urinary incontinence (Segal et al., InternationalPublication No. WO 00/61135). Prodrugs of GABA analogs such asgabapentin and pregabalin have also been used to treat patients whofrequently urinate but who do not have urinary incontinence orinvoluntary loss of urine (Thor et al., U.S. Patent Publication No.2004/0142034).

Although the mechanism of action of gabapentin in modulating theseaforementioned disease states (including urinary incontinence) is notunderstood with certainty, gabapentin, pregabalin and related analogsare known to interact with the α₂δ subunit of neuronal voltage-gatedcalcium channels (Gee et al., J. Biol. Chem. 1996, 271, 5768-5776;Bryans et al., J. Med. Chem. 1998, 41, 1838-1845). Methods ofadministering compounds such as GABA analogs (e.g., gabapentin,pregabalin, etc.) to a patient which modulate α₂δ subunits ofvoltage-gated calcium channels have been described (Guttuso, U.S. Pat.No. 6,310,098; Thor et al., supra).

One significant problem associated with the clinical use of many GABAanalogs, including gabapentin and pregabalin, is rapid systemicclearance. Consequently, these drugs require frequent dosing to maintaina therapeutic or prophylactic concentration in the systemic circulation(Bryans et al., Med. Res. Rev. 1999, 19, 149-177). For example, dosingregimens of 300-600 mg doses of gabapentin administered three times perday are typically used for anticonvulsive therapy. Higher doses(1800-3600 mg/day in three or four divided doses) are typically used forthe treatment of neuropathic pain states.

Although oral sustained released formulations are conventionally used toreduce the dosing frequency of drugs that exhibit rapid systemicclearance, oral sustained release formulations of gabapentin andpregabalin have not been developed because these drugs not absorbed viathe large intestine. Rather, these compounds are typically absorbed inthe small intestine by one or more amino acid transporters (e.g., the“large neutral amino acid transporter,” see Jezyk et al., Pharm. Res.1999, 16, 519-526). The limited residence time of both conventional andsustained release oral dosage forms in the proximal absorptive region ofthe gastrointestinal tract necessitates frequent daily dosing ofconventional oral dosage forms of these drugs, and has prevented thesuccessful application of sustained release technologies to many GABAanalogs.

One method for overcoming rapid systemic clearance of GABA analogsrelies upon the administration of an extended release dosage formulationcontaining a GABA analog prodrug (Gallop et al., InternationalPublication Nos. WO 02/100347 and WO 02/100349). Such prodrugs may beabsorbed over wider regions of the gastrointestinal tract than theparent drug, and across the wall of the colon where sustained releaseoral dosage forms typically spend a significant portion ofgastrointestinal transit time. These prodrugs are converted to theparent GABA analog upon absorption in vivo.

Current delivery techniques expose tissue outside of the desiredtreatment area (i.e., the urinary tract), to incontinence agents whichinefficiently uses the agents and dramatically increases the risk ofside effects. Therefore, there is a need in the art for a method ofdelivering an agent such as a prodrug of a GABA analog, particularly inextended release dosage form, which can treat and/or preventincontinence with a reduced risk of side effects.

3. SUMMARY

Methods of treating and/or preventing urinary incontinence are disclosedherein. The methods treat and/or prevent urinary incontinence in bothmale and female patients particularly in menopausal and post-menopausalhuman females. The methods find use in treating and/or preventingurinary incontinence characterized by symptoms of urinary frequency,mixed incontinence, urge incontinence and stress incontinence.

In one aspect, a method of treating and/or preventing urinaryincontinence in a patient which comprises administering to the patient atherapeutically effective amount of a prodrug of a GABA analog or apharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof isprovided.

In a second aspect, a method of treating and/or preventing urinaryincontinence in a patient comprising administering to the patient apharmaceutical composition which comprises a therapeutically effectiveamount of a prodrug of a GABA analog or a pharmaceutically acceptablesalt, hydrate, solvate or N-oxide thereof and a pharmaceuticallyacceptable vehicle is provided.

Methods disclosed herein are not restricted to particular prodrugs ofGABA analogs. Accordingly, the disclosed methods may be practiced withany GABA analog prodrug. In some embodiments, GABA analog prodrugs whichbind the α₂δ subunit of a voltage-gated calcium channel such as prodrugsof gabapentin and pregabalin are used to treat and/or prevent urinaryincontinence.

In other embodiments, the prodrug of a GABA analog has the structure ofFormula (I):

or a pharmaceutically acceptable salt, hydrate, solvate or N-oxidethereof, wherein:

n is 0 or 1;

Y is O or S;

R¹⁶ is hydrogen, alkyl or substituted alkyl;

R² is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, acyl, substituted acyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, oroptionally, R² and R¹⁶ together with the atoms to which they areattached form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

R³ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl and substituted heteroarylalkyl;

R⁴ and R⁵ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl or optionally, R⁴ and R⁵ together with the carbon atomto which they are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkylring;

R⁷ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;

R¹³ and R¹⁴ are each independently hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl,cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl or optionally, R¹³ andR¹⁴ together with the carbon atom to which they are attached form acycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substitutedcycloheteroalkyl ring; and

R²⁵ is selected from the group consisting of acyl, substituted acyl,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl.

In a third aspect, a pharmaceutical composition for treating a patientsuffering from urinary incontinence is provided. The pharmaceuticalcomposition comprises a therapeutically effective amount of a prodrug ofa GABA analog or a pharmaceutically acceptable salt, hydrate, solvate orN-oxide thereof and a pharmaceutically acceptable vehicle.

In a fourth aspect, a pharmaceutical composition for preventing urinaryincontinence in a patient at a risk of urinary incontinence is provided.The pharmaceutical composition comprises a therapeutically effectiveamount of a prodrug of a GABA analog or a pharmaceutically acceptablesalt, hydrate, solvate or N-oxide thereof and a pharmaceuticallyacceptable vehicle.

4. DETAILED DESCRIPTION 4.1 Definitions

“Compounds” refers to GABA analogs including any compounds encompassedby generic formulae disclosed herein. Compounds may be identified eitherby their chemical structure and/or chemical name. When the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the identity of the compound. Compounds describedherein may contain one or more chiral centers and/or double bonds andtherefore, may exist as stereoisomers, such as double-bond isomers(i.e., geometric isomers), enantiomers or diastereomers. Accordingly,the chemical structures depicted herein encompass all possibleenantiomers and stereoisomers of the illustrated compounds including thestereoisomerically pure form (e.g., geometrically pure, enantiomericallypure or diastereomerically pure) and enantiomeric and stereoisomericmixtures. Enantiomeric and stereoisomeric mixtures can be resolved intotheir component enantiomers or stereoisomers using separation techniquesor chiral synthesis techniques well known to the skilled artisan.Compounds may also exist in several tautomeric forms including the enolform, the keto form and mixtures thereof. Accordingly, the chemicalstructures depicted herein encompass all possible tautomeric forms ofthe illustrated compounds. Compounds described herein also includeisotopically labeled compounds where one or more atoms have an atomicmass different from the atomic mass conventionally found in nature.Examples of isotopes that may be incorporated into compounds disclosedherein include, but are not limited to, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, etc. Compounds may exist in unsolvated forms as well as solvatedforms, including hydrated forms and as N-oxides. In general, compoundsmay be hydrated, solvated or N-oxides. Certain compounds may exist inmultiple crystalline or amorphous forms. In general, all physical formsare equivalent for the uses contemplated herein and are intended to bewithin the scope of the present invention. Further, it should beunderstood, when partial structures of the compounds are illustrated,that brackets indicate the point of attachment of the partial structureto the rest of the molecule.

“Alkyl” by itself or as part of another substituent refers to asaturated or unsaturated, branched, straight-chain or cyclic monovalenthydrocarbon radical derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane, alkene or alkyne. Typical alkylgroups include, but are not limited to, methyl; ethyls such as ethanyl,ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl,cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl),cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl,prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

The term “alkyl” is specifically intended to include groups having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds and groupshaving mixtures of single, double and triple carbon-carbon bonds. Wherea specific level of saturation is intended, the expressions “alkanyl,”“alkenyl,” and “alkynyl” are used. In some embodiments, an alkyl groupcomprises from 1 to 20 carbon atoms. In other embodiments, an alkylgroup comprises from 1 to 10 carbon atoms. In still other embodiments,an alkyl group comprises from 1 to 6 carbon atoms.

“Alkanyl” by itself or as part of another substituent refers to asaturated branched, straight-chain or cyclic alkyl radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkane. Typical alkanyl groups include, but are not limited to,methanyl; ethanyl; propanyls such as propan-1-yl,propan-2-yl(isopropyl), cyclopropan-1-yl, etc.; butanyls such asbutan-1-yl, butan-2-yl(sec-butyl), 2-methyl-propan-1-yl(isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.

“Alkenyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon double bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkene. The groupmay be in either the cis or trans conformation about the double bond(s).Typical alkenyl groups include, but are not limited to, ethenyl;propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl),prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls suchas but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.;and the like.

“Alkynyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon triple bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkyne. Typicalalkynyl groups include, but are not limited to, ethynyl; propynyls suchas prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

“Acyl” by itself or as part of another substituent refers to a radical—C(O)R³⁰, where R³⁰ is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl,aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl as definedherein. Representative examples include, but are not limited to formyl,acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl,benzylcarbonyl and the like.

“Alkoxy” by itself or as part of another substituent refers to a radical—OR³¹ where R³¹ represents an alkyl or cycloalkyl group as definedherein. Representative examples include, but are not limited to,methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like.

“Alkoxycarbonyl” by itself or as part of another substituent refers to aradical —OR³² where R³² represents an alkyl or cycloalkyl group asdefined herein. Representative examples include, but are not limited to,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,cyclohexyloxycarbonyl and the like.

“Aryl” by itself or as part of another substituent refers to amonovalent aromatic hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ringsystem. Typical aryl groups include, but are not limited to, groupsderived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, coronene, fluoranthene,fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene,indane, indene, naphthalene, octacene, octaphene, octalene, ovalene,penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene,phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene,triphenylene, trinaphthalene and the like. In some embodiments, an arylgroup comprises from 6 to 20 carbon atoms. In other embodiments, an arylgroup comprises from 6 to 12 carbon atoms.

“Arylalkyl” by itself or as part of another substituent refers to anacyclic alkyl radical in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group. Typical arylalkyl groups include, but are not limited to,benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. Where specific alkyl moietiesare intended, the nomenclature arylalkanyl, arylalkenyl and/orarylalkynyl is used. In some embodiments, an arylalkyl group is (C₆-C₃₀)arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkylgroup is (C₁-C₁₀) and the aryl moiety is (C₆-C₂₀). In other embodiments,an arylalkyl group is (C₆-C₂₀) arylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the arylalkyl group is (C₁-C₈) and the aryl moiety is(C₆-C₁₂).

“AUC” is the area under the plasma drug concentration-versus-time curveextrapolated from zero time to infinity.

“Bridged cycloalkyl” refers to a radical selected from the groupconsisting of

wherein:

A is (CR³⁸R³⁹)_(b);

R³⁸ and R³⁹ are independently selected from the group consisting ofhydrogen and methyl;

R³⁶ and R³⁷ are independently selected from the group consisting ofhydrogen and methyl;

b is an integer from 1 to 4; and

c is an integer from 0 to 2.

“Carbamoyl” by itself or as part of another substituent refers to theradical —C(O)NR⁴⁰R⁴¹ where R⁴⁰ and R⁴¹ are independently hydrogen,alkyl, cycloalkyl or aryl as defined herein.

“C_(max)” is the highest drug concentration observed in plasma followingan extravascular dose of drug.

“Cycloalkyl” by itself or as part of another substituent refers to asaturated or unsaturated cyclic alkyl radical. Where a specific level ofsaturation is intended, the nomenclature “cycloalkanyl” or“cycloalkenyl” is used. Typical cycloalkyl groups include, but are notlimited to, groups derived from cyclopropane, cyclobutane, cyclopentane,cyclohexane and the like. Preferably, the cycloalkyl group is (C₃-C₁₀)cycloalkyl, more preferably (C₃-C₇) cycloalkyl.

“Cycloheteroalkyl” by itself or as part of another substituent refers toa saturated or unsaturated cyclic alkyl radical in which one or morecarbon atoms (and any associated hydrogen atoms) are independentlyreplaced with the same or different heteroatom. Typical heteroatoms toreplace the carbon atom(s) include, but are not limited to, N, P, O, S,Si, etc. Where a specific level of saturation is intended, thenomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl” is used.Typical cycloheteroalkyl groups include, but are not limited to, groupsderived from epoxides, azirines, thiiranes, imidazolidine, morpholine,piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, and thelike.

“GABA analog” refers to a compound, unless specified otherwise, ashaving the following structure:

wherein:

R is hydrogen, or R and R⁶ together with the atoms to which they areattached form an azetidine, substituted azetidine, pyrrolidine orsubstituted pyrrolidine ring;

R³ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl and substituted heteroarylalkyl; and

R⁴ and R⁵ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl or optionally, R⁴ and R⁵ together with the carbon atomto which they are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkylring.

“Heteroalkyl, Heteroalkanyl, Heteroalkenyl and Heteroalkynyl” bythemselves or as part of another substituent refer to alkyl, alkanyl,alkenyl and alkynyl groups, respectively, in which one or more of thecarbon atoms (and any associated hydrogen atoms) are independentlyreplaced with the same or different heteroatomic groups. Typicalheteroatomic groups which can be included in these groups include, butare not limited to, —O—, —S—, —O—O—, —S—S—, —O—S—, —NR⁴²R⁴³, —═N—N═—,—N═N—, —N═N—NR⁴⁴R⁴⁵, —PR⁴⁶—, —P(O)₂—, —POR⁴⁷—, —O—P(O)₂—, —SO—, —SO₂—,—SnR⁴⁸R⁴⁹— and the like, where R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸ and R⁴⁹are independently hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl.

“Heteroaryl” by itself or as part of another substituent refers to amonovalent heteroaromatic radical derived by the removal of one hydrogenatom from a single atom of a parent heteroaromatic ring system. Typicalheteroaryl groups include, but are not limited to, groups derived fromacridine, arsindole, carbazole, β-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. In some embodiments, the heteroaryl group is from 5-20 memberedheteroaryl. In other embodiments, the heteroaryl group is from 5-10membered heteroaryl. Preferred heteroaryl groups are those derived fromthiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine,quinoline, imidazole, oxazole and pyrazine.

“Heteroarylalkyl” by itself or as part of another substituent refers toan acyclic alkyl radical in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced with aheteroaryl group. Where specific alkyl moieties are intended, thenomenclature heteroarylalkanyl, heteroarylalkenyl and/orheterorylalkynyl is used. In some embodiments, the heteroarylalkyl groupis a 6-30 membered heteroarylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the heteroarylalkyl is 1-10 membered and theheteroaryl moiety is a 5-20-membered heteroaryl. In some embodiments,the heteroarylalkyl group is a 6-20 membered heteroarylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-8membered and the heteroaryl moiety is a 5-12-membered heteroaryl.

“Parent Aromatic Ring System” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more of the rings arearomatic and one or more of the rings are saturated or unsaturated, suchas, for example, fluorene, indane, indene, phenalene, etc. Typicalparent aromatic ring systems include, but are not limited to,aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene,trinaphthalene and the like.

“Parent Heteroaromatic Ring System” refers to a parent aromatic ringsystem in which one or more carbon atoms (and any associated hydrogenatoms) are independently replaced with the same or different heteroatom.Typical heteroatoms to replace the carbon atoms include, but are notlimited to, N, P, O, S, Si, etc. Specifically included within thedefinition of “parent heteroaromatic ring systems” are fused ringsystems in which one or more of the rings are aromatic and one or moreof the rings are saturated or unsaturated, such as, for example,arsindole, benzodioxan, benzofuran, chromane, chromene, indole,indoline, xanthene, etc. Typical parent heteroaromatic ring systemsinclude, but are not limited to, arsindole, carbazole, β-carboline,chromane, chromene, cinnoline, furan, imidazole, indazole, indole,indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like.

“Patient” refers to a mammal, which is preferably human.

“Pharmaceutically acceptable salt” refers to a salt of a compound, whichpossesses the desired pharmacological activity of the parent compound.Such salts include: (1) acid addition salts, formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound of the invention isadministered.

“Patient” includes humans. The terms “human” and “patient” are usedinterchangeably herein.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease).

“Prodrug” refers to a derivative of a drug molecule that requires atransformation within the body to release the active drug. Prodrugs arefrequently, although not necessarily, pharmacologically inactive untilconverted to the parent drug. A hydroxyl containing drug may beconverted to, for example, to a sulfonate, ester or carbonate prodrug,which may be hydrolyzed in vivo to provide the hydroxyl compound. Anamino containing drug may be converted, for example, to a carbamate,amide, enamine, imine, N-phosphonyl, N-phosphoryl or N-sulfenyl prodrug,which may be hydrolyzed in vivo to provide the amino compound. Acarboxylic acid drug may be converted to an ester (including silylesters and thioesters), amide or hydrazide prodrug, which be hydrolyzedin vivo to provide the carboxylic acid compound. Prodrugs for drugswhich have functional groups different than those listed above are wellknown to the skilled artisan.

“Promoiety” refers to a form of protecting group that when used to maska functional group within a drug molecule converts the drug into aprodrug. Typically, the promoiety will be attached to the drug viabond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.

“Protecting group” refers to a grouping of atoms that when attached to areactive functional group in a molecule masks, reduces or preventsreactivity of the functional group. Examples of protecting groups can befound in Green et al., “Protective Groups in Organic Chemistry”, (Wiley,2^(nd) ed. 1991) and Harrison et al., “Compendium of Synthetic OrganicMethods”, Vols. 1-8 (John Wiley and Sons, 1971-1996). Representativeamino protecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“SES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxy protecting groups include,but are not limited to, those where the hydroxy group is either acylatedor alkylated such as benzyl, and trityl ethers as well as alkyl ethers,tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

“Substituted” refers to a group in which one or more hydrogen atoms areindependently replaced with the same or different substituent(s).Typical substituents include, but are not limited to, -M, —R⁶⁰, —O⁻, ═O,—OR⁶⁰, —SR⁶⁰, —S⁻, ═S, —NR⁶⁰R⁶¹, ═NR⁶⁰, —CF₃, —CN, —OCN, —SCN, —NO,—NO₂, ═N₂, —N₃, —S(O)₂O⁻, —S(O)₂OH, —S(O)₂R⁶⁰, —OS(O₂)O⁻, —OS(O)₂R⁶⁰,—P(O)(O⁻)₂, —P(O)(OR⁶⁰)(O⁻), —OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰, —C(S)R⁶⁰,—C(O)OR⁶⁰, —C(O)NR⁶⁰R⁶¹, —C(O)O⁻, —C(S)OR⁶⁰, —NR⁶²C(O)NR⁶⁰R⁶¹,—NR⁶²C(S)NR⁶⁰R⁶¹, NR⁶²C(NR⁶³)NR⁶⁰R⁶¹ and —C(NR⁶²)NR⁶⁰R⁶¹ where M isindependently a halogen; R⁶⁰, R⁶¹, R⁶² and R⁶³ are independentlyhydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl, or optionally R⁶⁰ and R⁶¹ together with the nitrogen atom towhich they are bonded form a cycloheteroalkyl or substitutedcycloheteroalkyl ring; and R⁶⁴ and R⁶⁵ are independently hydrogen,alkyl, substituted alkyl, aryl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl, or optionally R⁶⁴ and R⁶⁵ togetherwith the nitrogen atom to which they are bonded form a cycloheteroalkylor substituted cycloheteroalkyl ring. Preferably, substituents include-M, —R⁶⁰, ═O, —OR⁶⁰, —SR⁶⁰, —S⁻, ═S, —NR⁶⁰R⁶¹, ═NR⁶⁰, —CF₃, —CN, —OCN,—SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)₂R⁶⁰, —OS(O₂)O⁻, —OS(O)₂R⁶⁰, —P(O)(O⁻)₂,—P(O)(OR⁶⁰)(O⁻), —OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰, —C(S)R⁶⁰, —C(O)OR⁶⁰,—C(O)NR⁶⁰R⁶¹, —C(O)O⁻, —NR⁶²C(O)NR⁶⁰R⁶¹, more preferably, -M, —R⁶⁰, ═O,—OR⁶⁰, —SR⁶⁰, —NR⁶⁰R⁶¹, —CF₃, —CN, —NO₂, —S(O)₂R⁶⁰, —P(O)(OR⁶⁰)(O⁻),—OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)NR⁶⁰R⁶¹, —C(O)O⁻, mostpreferably, -M, —R⁶⁰, ═O, —OR⁶⁰, —SR⁶⁰, —NR⁶⁰R⁶¹, —CF₃, —CN, —NO₂,—S(O)₂R⁶⁰, —OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)O⁻, where R⁶⁰,R⁶¹ and R⁶² are as defined above.

“Sustained release” refers to release of an agent from a dosage form ata rate effective to achieve a therapeutic or prophylactic amount of theagent, or active metabolite thereof, in the systemic blood circulationover a prolonged period of time relative to that achieved by oraladministration of a conventional formulation of the agent. In someembodiments, release of the agent occurs over a period of at least 6hours. In other embodiments, release of the agent occurs over a periodof at least 8 hours. In still other embodiments, release of the agentoccurs over a period of at least 12 hours.

“Treating” or “treatment” of any disease or disorder refers, in someembodiments, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In other embodiments “treating” or “treatment” refersto ameliorating at least one physical parameter, which may not bediscernible by the patient. In yet other embodiments, “treating” or“treatment” refers to inhibiting the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter) or both.In yet other embodiments, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

“Therapeutically effective amount” means the amount of a compound that,when administered to a patient for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” will vary depending on the compound, the disease and itsseverity and the age, weight, etc., of the patient to be treated.

“Urinary incontinence” refers to the involuntary loss of urine from thebladder.

Reference will now be made in detail to preferred embodiments of theinvention. While the invention will be described in conjunction with thepreferred embodiments, it will be understood that it is not intended tolimit the invention to those preferred embodiments. To the contrary, itis intended to cover alternatives, modifications, and equivalents as maybe included within the spirit and scope of the invention as defined bythe appended claims.

4.2 GABA Analog Prodrugs

In some embodiments, a prodrug of a GABA analog has the structure ofFormula (I):

or a pharmaceutically acceptable salt, hydrate, solvate or N-oxidethereof, wherein:

n is 0 or 1;

Y is O or S;

R¹⁶ is hydrogen, alkyl or substituted alkyl;

R² is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, acyl, substituted acyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, oroptionally, R² and R¹⁶ together with the atoms to which they areattached form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

R³ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl and substituted heteroarylalkyl;

R⁴ and R⁵ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl or optionally, R⁴ and R⁵ together with the carbon atomto which they are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkylring;

R⁷ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;

R¹³ and R¹⁴ are each independently hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl,cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl or optionally, R¹³ andR¹⁴ together with the carbon atom to which they are attached form acycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substitutedcycloheteroalkyl ring; and

R²⁵ is selected from the group consisting of acyl, substituted acyl,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl.

In some embodiments, R¹³ and R¹⁴ are independently hydrogen, alkyl,substituted alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl,cycloalkyl, substituted cycloalkyl, or heteroaryl (preferably, when R¹³is alkoxycarbonyl or carbamoyl then R¹⁴ is methyl). In otherembodiments, R¹³ and R¹⁴ are independently hydrogen, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl,cyclohexyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl,benzyl, phenethyl or 3-pyridyl.

In still other embodiments, R¹³ and R¹⁴ are independently hydrogen,alkanyl, substituted alkanyl, cycloalkanyl or substituted cycloalkanyl.In still other embodiments, R¹³ and R¹⁴ are hydrogen, alkanyl orcycloalkanyl. In still other embodiments, R¹³ and R¹⁴ are independentlyhydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclopentyl or cyclohexyl. In still other embodiments, R¹³is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclopentyl or cyclohexyl and R¹⁴ is hydrogen, or R¹³ ismethyl and R¹⁴ is methyl.

In still other embodiments, R¹³ and R¹⁴ are independently hydrogen,aryl, arylalkyl or heteroaryl. In still other embodiments, R¹³ and R¹⁴are independently hydrogen, phenyl, benzyl, phenethyl or 3-pyridyl. Instill other embodiments, R¹³ is phenyl, benzyl, phenethyl or 3-pyridyland R¹⁴ is hydrogen.

In still other embodiments, R¹³ and R¹⁴ are independently hydrogen,alkyl, substituted alkyl, alkoxycarbonyl or carbamoyl. In still otherembodiments, R¹³ is alkoxycarbonyl or carbamoyl and R¹⁴ is methyl. Instill other embodiments, R¹³ is methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl or cyclohexyloxycarbonyl and R¹⁴is methyl.

In still other embodiments, R¹³ and R¹⁴ together with the carbon atom towhich they are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring. In still otherembodiments, R¹³ and R¹⁴ together with the carbon atom to which they areattached form a cycloalkyl ring. In still other embodiments, R¹³ and R¹⁴together with the carbon atom to which they are attached form acyclobutyl, cyclopentyl or cyclohexyl ring.

In still other embodiments of compounds of Formula (I), R²⁵ is acyl,substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkylor heteroaryl. In still other embodiments, R²⁵ is methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In still other embodiments, R²⁵ is acyl or substituted acyl. In stillother embodiments, R²⁵ is acetyl, propionyl, butyryl, benzoyl orphenacetyl.

In still other embodiments, R²⁵ is alkanyl or substituted alkanyl. Instill other embodiments, R²⁵ is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl or 1-(1,3-dioxan-2-yl)-2-phenethyl. Instill other embodiments, R²⁵ is methyl, ethyl, propyl, isopropyl, butyl,1,1-dimethoxyethyl or 1,1-diethoxyethyl.

In still other embodiments, R²⁵ is aryl, arylalkyl or heteroaryl. Instill other embodiments, R²⁵ is phenyl, 4-methoxyphenyl, benzyl,phenethyl, styryl or 3-pyridyl.

In still other embodiments, R²⁵ is cycloalkyl or substituted cycloalkyl.In still other embodiments, R²⁵ is cyclopropyl, cyclobutyl, cyclopentylor cyclohexyl.

In still other embodiments, R²⁵ is acyl, substituted acyl, alkyl,substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R¹³ andR¹⁴ are independently hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl, or heteroaryl(preferably, R¹³ is alkoxycarbonyl or carbamoyl and R¹⁴ is methyl). Instill other embodiments, R²⁵ is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or 3-pyridyl and R¹³ and R¹⁴ are independentlyhydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl,benzyl, phenethyl or 3-pyridyl. In still other embodiments, R²⁵ ismethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1,1-dimethoxybenzyl,1,1-diethoxybenzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, cyclohexyl or 3-pyridyl and R¹³ andR¹⁴ are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl or 3-pyridyl.

In still other embodiments, R²⁵ is acyl, substituted acyl, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl and R¹³ and R¹⁴ together with the atom to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. In still other embodiments, R²⁵ isacyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl,cycloalkyl or heteroaryl and R¹³ and R¹⁴ together with the atom to whichthey are attached form a cycloalkyl or substituted cycloalkyl ring. Instill other embodiments, R²⁵ is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or 3-pyridyl and R¹³ and R¹⁴ together with theatom to which they are attached form a cyclobutyl, cyclopentyl or acyclohexyl ring.

In still other embodiments, R²⁵ is acyl or substituted acyl and R¹³ andR¹⁴ are independently hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl,cycloalkyl, substituted cycloalkyl, heteroaryl or substituted heteroaryl(preferably, when R¹³ is alkoxycarbonyl, substituted alkoxycarbonyl,carbamoyl or substituted carbamoyl then R¹⁴ is methyl). In still otherembodiments, R²⁵ is acetyl, propionyl, butyryl, benzoyl or phenacetyl,and R¹³ and R¹⁴ are independently hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl,cycloalkyl, substituted cycloalkyl, heteroaryl or substituted heteroaryl(preferably, when R¹³ is alkoxycarbonyl, or carbamoyl then R¹⁴ ismethyl).

In still other embodiments, R²⁵ is alkanyl or substituted alkanyl andR¹³ and R¹⁴ are independently hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl,cycloalkyl, substituted cycloalkyl, heteroaryl or substituted heteroaryl(preferably, when R¹³ is alkoxycarbonyl, substituted alkoxycarbonyl,carbamoyl or substituted carbamoyl then R¹⁴ is methyl). In still otherembodiments, R²⁵ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl or 1-(1,3-dioxan-2-yl)-2-phenethyl andR¹³ and R¹⁴ are independently hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl,cycloalkyl, substituted cycloalkyl, heteroaryl or substituted heteroaryl(preferably, when R¹³ is alkoxycarbonyl or carbamoyl then R¹⁴ ismethyl).

In still other embodiments, R²⁵ is aryl, substituted aryl, arylalkyl,substituted arylalkyl, heteroaryl or substituted heteroaryl and R¹³ andR¹⁴ are independently hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substitutedcycloalkyl, heteroaryl or substituted heteroaryl (preferably, when R¹³is alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl or substitutedcarbamoyl then R¹⁴ is methyl). In still other embodiments, R²⁵ isphenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl and R¹³and R¹⁴ are independently hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substitutedcycloalkyl, heteroaryl or substituted heteroaryl (preferably, when R¹³is alkoxycarbonyl or carbamoyl then R¹⁴ is methyl).

In still other embodiments, R²⁵ is cycloalkyl or substituted cycloalkyl,and R¹³ and R¹⁴ are independently hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substitutedcycloalkyl, heteroaryl or substituted heteroaryl (preferably, when R¹³is alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl or substitutedcarbamoyl then R¹⁴ is methyl). Preferably, R²⁵ is cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl and R¹³ and R¹⁴ are independentlyhydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, heteroaryl orsubstituted heteroaryl (preferably, when R¹³ is alkoxycarbonyl, orcarbamoyl then R¹⁴ is methyl).

In still other embodiments, R²⁵ is acyl, substituted acyl, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl, and R¹³ and R¹⁴ are independently hydrogen, alkyl,substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl. In stillother embodiments, R²⁵ is acyl, substituted acyl, alkyl, substitutedalkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R¹³ and R¹⁴ areindependently hydrogen, alkanyl, substituted alkanyl, cycloalkanyl orsubstituted cycloalkanyl. In still other embodiments, R²⁵ is acyl,substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkylor heteroaryl and R¹³ and R¹⁴ are independently hydrogen, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentylor cyclohexyl. In the above embodiments, R²⁵ is preferably methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In still other embodiments, R²⁵ is acyl, substituted acyl, alkyl,substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R¹³ andR¹⁴ are independently hydrogen, alkyl, substituted alkyl, aryl,arylalkyl, cycloalkyl or heteroaryl. In still other embodiments, R²⁵ isacyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl,cycloalkyl or heteroaryl and R¹³ and R¹⁴ are independently hydrogen,aryl, arylalkyl or heteroaryl. In still other embodiments, R²⁵ is acyl,substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkylor heteroaryl and R¹³ and R¹⁴ are independently hydrogen, phenyl,benzyl, phenethyl or 3-pyridyl. In still other embodiments, R²⁵ ispreferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or 3-pyridyl.

In still other embodiments, R²⁵ is acyl, substituted acyl, alkyl,substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R¹³ andR¹⁴ are independently hydrogen, alkyl, substituted alkyl, aryl,arylalkyl, cycloalkyl or heteroaryl. In still other embodiments, R²⁵ isacyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl,cycloalkyl or heteroaryl and R¹³ and R¹⁴ are independently hydrogen,alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl,carbamoyl or substituted carbamoyl, (preferably, when R¹³ isalkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl or substitutedcarbamoyl then R¹⁴ is methyl, more preferably, R¹³ is methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl orcyclohexyloxycarbonyl, and R¹⁴ is methyl). In the above embodiments, R²⁵is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or 3-pyridyl.

In still other embodiments, R²⁵ is acyl, substituted acyl, alkyl,substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R¹³ andR¹⁴ together with the atom to which they are attached form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring. In still other embodiments, R²⁵ is acyl, substituted acyl, alkyl,substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R¹³ andR¹⁴ together with the atom to which they are attached form a cycloalkylor substituted cycloalkyl ring. In still other embodiments, R²⁵ is acyl,substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkylor heteroaryl, and R¹³ and R¹⁴ together with the atom to which they areattached form a cyclobutyl, cyclopentyl or cyclohexyl ring. In stillother embodiments, R²⁵ is preferably methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or 3-pyridyl.

In still other embodiments of compounds of Formula (I), R⁴ and R⁵together with the carbon atom to which they are attached form acyclobutyl or substituted cyclobutyl ring. In still other embodiments,the substituted cyclobutyl ring is substituted with one or moresubstituents selected from the group consisting of alkanyl, substitutedalkanyl, halo, hydroxy, carboxy and alkoxycarbonyl.

In still other embodiments of compounds of Formula (I), R⁴ and R⁵together with the carbon atom to which they are attached form acyclopentyl or substituted cyclopentyl ring In still other embodiments,the cyclopentyl ring is substituted with alkanyl, substituted alkanyl,halo, hydroxy, carboxy or alkoxycarbonyl. In still other embodiments,the cyclopentyl ring is substituted with alkanyl. In still otherembodiments, the cyclopentyl ring is selected from the group consistingof

In a more specific version of the above embodiments, R⁷ is hydrogen.

In still other embodiments of compounds of Formula (I), R⁴ and R⁵together with the carbon atom to which they are attached form acyclohexyl or substituted cyclohexyl ring. In still other embodiments,the cyclohexyl ring is substituted with alkanyl, substituted alkanyl,halo, hydroxy, carboxy or alkoxycarbonyl. In still other embodiments,the cyclohexyl ring is substituted with alkanyl. In still otherembodiments, the cyclohexyl ring is selected from the group consistingof

In a more specific version of the above embodiments, R⁷ is hydrogen.

In still other embodiments of compounds of Formula (I), R⁴ and R⁵together with the carbon atom to which they are attached form acycloheteroalkyl or substituted cycloheteroalkyl ring. In someembodiments, n is 0. In other embodiments, n is 1, and R² is hydrogen,methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl,phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl, 3-indolylmethyl,—CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂,—CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂. In stillother embodiments, n is 1 and R² and R¹⁶ together with the atoms towhich they are attached form a pyrrolidine ring. Preferably, R⁴ and R⁵together with the carbon atom to which they are attached form acycloheteroalkanyl ring. More preferably, the cycloheteroalkanyl ring isselected from the group consisting of

wherein Z is O, S(O)_(p) or NR¹⁸;

p is 0, 1 or 2; and

R¹⁸ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, acyl and alkoxycarbonyl. More preferably, thecycloheteroalkanyl ring is selected from the group consisting of

In a more specific version of the above embodiments, R⁷ is hydrogen.

In still other embodiments of compounds of Formula (I), R⁴ and R⁵together with the carbon atom to which they are attached form a bridgedcycloalkyl ring. In some embodiments, n is 0. In other embodiments, n is1 and R² is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl,cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl, 3-indolylmethyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H,—CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂or —CH₂CH₂CH₂NHC(NH)NH₂. In other embodiments, n is 1 and R² and R¹⁶together with the atoms to which they are attached form a pyrrolidinering. Preferably, the bridged cycloalkyl group is

In a more specific version of the above embodiments, R⁷ is hydrogen.

In still other embodiments of compounds of Formula (I), Y is O, R⁶ andR⁷ are hydrogen, R⁴ is alkyl or cycloalkyl, R⁵ is hydrogen or alkyl andR³ is hydrogen or alkyl. In some embodiments, n is 0. In otherembodiments, n is 1 and R² is hydrogen, methyl, 2-propyl, 2-butyl,isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl,4-hydroxybenzyl, 4-imidazolylmethyl, 3-indolylmethyl, —CH₂OH,—CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃,—CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂. In still otherembodiments, n is 1 and R² and R¹⁶ together with the atoms to which theyare attached form a pyrrolidine ring. Preferably, R⁴ is cycloalkyl, R⁵is hydrogen or methyl, and R³ is hydrogen or methyl. Preferably, R³ ishydrogen, R⁴ is isobutyl and R⁵ is hydrogen.

In still other embodiments of compounds of Formula (I), Y is O, R⁵ andR⁷ are hydrogen or alkanyl, R³ and R⁶ are hydrogen and R⁴ is substitutedheteroalkyl. Preferably, R⁴ is

A is NR¹⁹, O or S;

B is alkyl, substituted alkyl, alkoxy, halogen, hydroxy, carboxy,alkoxycarbonyl or amino;

R¹⁹ is hydrogen, alkyl, cycloalkyl or aryl;

j is an integer from 0 to 4;

k is an integer from 1 to 4; and

l is an integer from 0 to 3.

More preferably, k is 1.

In still other embodiments of compounds of Formula (I), Y is O, R⁵ andR⁷ are hydrogen or alkanyl, R³ and R⁶ are hydrogen and R⁴ is substitutedalkanyl, cycloalkanyl or substituted cycloalkanyl. Preferably, R⁴ isselected from the group consisting of

Preferably, R⁴ is

h is an integer from 1 to 6; and

i is an integer from 0 to 6.

More preferably, h is 1, 2, 3 or 4 and i is 0 or 1. Even morepreferably, R⁴ is selected from the group consisting of

Preferably, compounds of Formula (I) are derived from a GABA analog ofFormula (IV):

wherein the GABA analog of Formula (IV) is selected from the groupconsisting of:

-   1-Aminomethyl-1-cyclohexane acetic acid (i.e., gabapentin);-   1-Aminomethyl-1-(3-methylcyclohexane)acetic acid;-   1-Aminomethyl-1-(4-methylcyclohexane)acetic acid;-   1-Aminomethyl-1-(4-isopropylcyclohexane)acetic acid;-   1-Aminomethyl-1-(4-tert-butylcyclohexane)acetic acid;-   1-Aminomethyl-1-(3,3-dimethylcyclohexane)acetic acid;-   1-Aminomethyl-1-(3,3,5,5-tetramethylcyclohexane)acetic acid;-   1-Aminomethyl-1-cyclopentane acetic acid;-   1-Aminomethyl-1-(3-methylcyclopentane)acetic acid;-   1-Aminomethyl-1-(3,4-dimethylcyclopentane)acetic acid;-   7-Aminomethyl-bicyclo[2.2.1]hept-7-yl acetic acid;-   9-Aminomethyl-bicyclo[3.3.1]non-9-yl acetic acid;-   4-Aminomethyl-4-(tetrahydropyran-4-yl)acetic acid;-   3-Aminomethyl-3-(tetrahydropyran-3-yl)acetic acid;-   4-Aminomethyl-4-(tetrahydrothiopyran-4-yl)acetic acid;-   3-Aminomethyl-3-(tetrahydrothiopyran-3-yl)acetic acid;-   (S)-3-Aminomethyl-5-methyl-hexanoic acid (i.e., pregabalin);-   3-Aminomethyl-5-methyl-heptanoic acid;-   3-Aminomethyl-5-methyl-octanoic acid;-   3-Aminomethyl-5-methyl-nonanoic acid;-   3-Aminomethyl-5-methyl-decanoic acid;-   3-Aminomethyl-5-cyclopropyl-hexanoic acid;-   3-Aminomethyl-5-cyclobutyl-hexanoic acid;-   3-Aminomethyl-5-cyclopentyl-hexanoic acid;-   3-Aminomethyl-5-cyclohexyl-hexanoic acid;-   3-Aminomethyl-5-phenyl-hexanoic acid;-   3-Aminomethyl-5-phenyl-pentanoic acid;-   3-Aminomethyl-4-cyclobutyl-butyric acid;-   3-Aminomethyl-4-cyclopentyl-butyric acid;-   3-Aminomethyl-4-cyclohexyl-butyric acid;-   3-Aminomethyl-4-phenoxy-butyric acid;-   3-Aminomethyl-5-phenoxy-hexanoic acid; and-   3-Aminomethyl-5-benzylsulfanyl-pentanoic acid.

In still other embodiments, compounds of Formula (I) have the structureof Formulae (II) and (III):

wherein n, R², R⁷, R¹³, R¹⁴, R¹⁶ and R²⁵ are as previously defined.

In some embodiments of compounds of Formulae (II) and (III), n is 0. Inother embodiments, n is 1. When n is 1, preferably, the α-amino acid isof the L-stereochemical configuration.

In still other embodiments of compounds of Formulae (II) and (III), n is1, R¹⁶ is hydrogen and R² is hydrogen, methyl, 2-propyl, 2-butyl,isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl,4-hydroxybenzyl, 4-imidazolylmethyl, 3-indolylmethyl, —CH₂OH,—CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃,—CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂. In still otherembodiments, R¹⁶ is hydrogen and R² is hydrogen, methyl, 2-propyl,2-butyl, isobutyl, tert-butyl, cyclohexyl, phenyl or benzyl. In stillother embodiments, n is 1 and R² and R¹⁶ together with the atoms towhich they are attached form a pyrrolidine ring.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ ishydrogen and R¹⁴ is hydrogen.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ ismethyl and R¹⁴ is hydrogen.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isethyl and R¹⁴ is hydrogen.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ ispropyl and R¹⁴ is hydrogen.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isisopropyl and R¹⁴ is hydrogen.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isbutyl and R¹⁴ is hydrogen.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isisobutyl and R¹⁴ is hydrogen.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ issec-butyl and R¹⁴ is hydrogen.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ istert-butyl and R¹⁴ is hydrogen.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ iscyclopentyl and R¹⁴ is hydrogen.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ iscyclohexyl and R¹⁴ is hydrogen.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ ismethyl and R¹⁴ is methyl.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ ismethoxycarbonyl and R¹⁴ is methyl.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isethoxycarbonyl and R¹⁴ is methyl.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵,is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ ispropoxycarbonyl and R¹⁴ is methyl.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isisopropoxycarbonyl and R¹⁴ is methyl.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isbutoxycarbonyl and R¹⁴ is methyl.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isisobutoxycarbonyl and R¹⁴ is methyl.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ issec-butoxycarbonyl and R¹⁴ is methyl.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ istert-butoxycarbonyl and R¹⁴ is methyl.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ iscyclohexyloxycarbonyl and R¹⁴ is methyl.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isphenyl and R¹⁴ is hydrogen.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isbenzyl and R¹⁴ is hydrogen.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isphenethyl and R¹⁴ is hydrogen.

In still other embodiments of compounds of Formulae (II) and (III), R²⁵is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ is3-pyridyl and R¹⁴ is hydrogen.

In some of the embodiments described, supra, for R¹³, R¹⁴ and R²⁵ forcompounds of Formulae (II) and (III), R⁷ is hydrogen.

In still other embodiments, compounds of Formulae (II) and (III) havethe structure of Formulae (V) and (VI), respectively

or a pharmaceutically acceptable salt, hydrate, solvate or N-oxidethereof where wherein R¹³, R¹⁴ and R²⁵ are as previously defined. Thoseof skill in the art will appreciate that the embodiments described,supra, for R¹³, R¹⁴ and R²⁵ for compounds of Formulae (II) and (III) arealso embodiments for compounds of Formulae (V) and (VI). In some ofthese embodiments R⁷ is hydrogen.

In some embodiments of compounds of Formulae (V) and (VI), R⁷ and R¹⁴are each hydrogen, R¹³ is C₁-C₆ alkyl and R²⁵ is C₁-C₆ alkyl or C₁-C₆substituted alkyl. In some embodiments, R¹³ is selected from the groupconsisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl andsec-butyl and R²⁵ is selected from the group consisting of methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl,isopentyl, sec-pentyl, neopentyl and 1,1-diethoxyethyl.

In some embodiments of compounds of Formulae (V) and (VI), R¹³ ismethyl. In other embodiments of compound of compounds of Formulae (V)and (VI), R²⁵ is methyl, ethyl, n-propyl or isopropyl. In still otherembodiments of compounds of Formulae (V) and (VI), R¹³ is methyl and R²⁵is methyl, ethyl, n-propyl or n-butyl. In still other embodiments ofcompounds of Formulae (V) and (VI), R¹³ is ethyl and R²⁵ is methyl,n-propyl or isopropyl. In still other embodiments of compounds ofFormulae (V) and (VI), R¹³ is n-propyl and R²⁵ is methyl, ethyl,n-propyl, isopropyl or n-butyl. In still other embodiments of compoundsof Formulae (V) and (VI), R¹³ is isopropyl and R²⁵ is methyl, ethyl,n-propyl, isopropyl, n-butyl or isobutyl. In still other embodiments ofcompounds of Formulae (V) and (VI), R¹³ is n-propyl and R²⁵ is n-propyl.In still other embodiments of compounds of Formulae (V) and (VI), R¹³ ismethyl and R²⁵ is ethyl. In still other embodiments of compounds ofFormulae (V) and (VI), R¹³ is methyl and R²⁵ is isopropyl. In stillother embodiments of compounds of Formulae (V) and (VI), R¹³ isisopropyl and R²⁵ is isopropyl. In still other embodiments of compoundsof Formulae (V) and (VI), R¹³ is isopropyl and R²⁵ is 1,1-diethoxyethyl.In still other embodiments of compounds of Formulae (V) and (VI), R¹³ ispropyl and R²⁵ is isopropyl. In still other embodiments of compounds ofFormulae (V) and (VI), R¹³ is propyl and R²⁵ is ethyl.

In some embodiments, the compound of Formula (V) where R²⁵ is isopropyl,R¹³ is methyl and R¹⁴ is hydrogen is a crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid as disclosed in Estrada et al., U.S. patent application Ser. No.10/966,507, which claims the benefit of U.S. Provisional ApplicationSer. No. 60/511,287, filed Oct. 14, 2003.

Specific examples of Formula (V) compounds include1-{[α-acetoxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid,1-{[(α-propanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, 1-{[(α-butanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid,1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, 1-{[(α-pivaloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, 1-{[α-acetoxymethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, 1-{[(α-propanoyloxymethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid,1-{[(α-butanoyloxymethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, 1-{[(α-isobutanoyloxymethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid, 1-{[(α-pivaloxymethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid, 1-{[α-acetoxypropoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid,1-{[(α-propanoyloxypropoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, 1-{[(α-butanoyloxypropoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid,1-{[(α-isobutanoyloxypropoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, 1-{[(α-pivaloxypropoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, 1-{[α-acetoxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, 1-{[(α-propanoyloxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid,1-{[(α-butanoyloxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid,1-{[(α-isobutanoyloxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid,1-{[(α-pivaloxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, 1-{[α-acetoxybutoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, 1-{[(α-propanoyloxybutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid 1-{[(α-butanoyloxybutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid1-{[(α-isobutanoyloxybutoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and 1-{[(α-pivaloxybutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid.

Specific examples of Formula (VI) compounds include3-{[α-acetoxyethoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid,3-{[(α-propanoyloxyethoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid,3-{[(α-butanoyloxyethoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid,3-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-5-methyl hexanoicacid, 3-{[(α-pivaloxyethoxy)carbonyl]aminomethyl}-5-methyl hexanoicacid, 3-{[α-acetoxymethoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid,3-{[(α-propanoyloxymethoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid,3-{[(α-butanoyloxymethoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid,3-{[(α-isobutanoyloxymethoxy)carbonyl]aminomethyl}-5-methyl hexanoicacid, 3-{[(α-pivaloxymethoxy)carbonyl]aminomethyl}-5-methyl hexanoicacid, 3-{[α-acetoxypropoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid,3-{[(α-propanoyloxypropoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid,3-{[(α-butanoyloxypropoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid,3-{[(α-isobutanoyloxypropoxy)carbonyl]aminomethyl}-5-methyl hexanoicacid, 3-{[(α-pivaloxypropoxy)carbonyl]aminomethyl}-5-methyl hexanoicacid, 3-{[α-acetoxyisopropoxy)carbonyl]aminomethyl}-5-methyl hexanoicacid, 3-{[(α-propanoyloxyisopropoxy)carbonyl]aminomethyl}-5-methylhexanoic acid,3-{[(α-butanoyloxyisopropoxy)carbonyl]aminomethyl}-5-methyl hexanoicacid, 3-{[(α-isobutanoyloxyisopropoxy)carbonyl]aminomethyl}-5-methylhexanoic acid, 3-{[(α-pivaloxyisopropoxy)carbonyl]aminomethyl}-5-methylhexanoic acid, 3-{[(α-acetoxybutoxy)carbonyl]aminomethyl}-5-methylhexanoic acid, 3-{[(α-propanoyloxybutoxy)carbonyl]aminomethyl}-5-methylhexanoic acid, 3-{[(α-butanoyloxybutoxy)carbonyl]aminomethyl}-5-methylhexanoic acid,3-{[(α-isobutanoyloxybutoxy)carbonyl]aminomethyl}-5-methyl hexanoic acidand 3-{[(α-pivaloxybutoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid.

4.3 Methods of Synthesis of Prodrugs of GABA Analogs

Methods of synthesis of prodrugs of GABA analogs, including methods ofsynthesizing compounds of structural Formulae (I), (II), (III), (V) and(VI) are disclosed in Gallop et al., International Publication No. WO02/100347, Gallop et al., U.S. application Ser. No. 10/313,825, filedDec. 6, 2002 and Bhat et al., U.S. patent application Ser. No.10/893,130, filed Jul. 15, 2004. Other methods for synthesis of prodrugsof GABA analogs have also been disclosed (see Bryans et al.,International Publication No. WO 01/90052; U.K. Application GB2,362,646; European Applications EP 1,201,240 and 1,178,034; Yatvin etal., U.S. Pat. No. 6,024,977; Gallop et al., International PublicationNo. WO 02/28881; Gallop et al., International Publication No. WO02/28883; Gallop et al., International Publication No. WO 02/28411;Gallop et al., International Publication No. WO 02/32376; Gallop et al.,International Publication No. WO 02/42414).

4.4 Therapeutic/Prophylactic Administration

Dosage forms comprising prodrugs of GABA analogs may be advantageouslyused to treat and/or prevent urinary incontinence. The dosage forms maybe administered or applied singly, or in combination with other agents.The dosage forms may also deliver a prodrug of a GABA analog to apatient in combination with another pharmaceutically active agent,including another prodrug of a GABA analog. The patient is a mammal,preferably, a human.

When used in the present methods of treatment, the dosage forms uponreleasing a prodrug of a GABA analog in vivo preferably, provide theGABA analog (e.g., gabapentin or pregabalin) in the systemic circulationof the patient. While not wishing to bound by theory, the promoiety orpromoieties of the prodrug may be cleaved either chemically and/orenzymatically. One or more enzymes present in the stomach, intestinallumen, intestinal tissue, blood, liver, brain or any other suitabletissue of a mammal may cleave the promoiety or promoieties of theprodrug. The mechanism of cleavage is not important to the currentmethods. Preferably, the GABA analog that is formed by cleavage of thepromoiety from the prodrug does not contain substantial quantities oflactam contaminant (preferably, less than about 0.5% by weight, morepreferably, less than about 0.2% by weight, most preferably, less thanabout 0.1% by weight) for the reasons described in Augart et al., U.S.Pat. No. 6,054,482. The extent of release of lactam contaminant from theprodrugs may be assessed using standard in vitro analytical methods.

Some therapeutically effective GABA analogs, e.g., gabapentin andpregabalin, have poor passive permeability across the gastrointestinalmucosa, probably because of their zwitterionic character atphysiological pH. Gabapentin, pregabalin and other GABA analogs areactively transported across the gastrointestinal tract by one or moreamino acid transporters (e.g., the “large neutral amino acidtransporter”). However, the large neutral amino acid transporter isexpressed predominantly within cells lining the lumen of a limitedregion of the small intestine, which provides limited window for drugabsorption and leads to an overall dose-dependent drug bioavailabilitythat decreases with increasing dose.

Because the compounds disclosed herein can be formulated in sustainedrelease formulations which provide for sustained release over a periodof hours into the gastrointestinal tract and particularly, releasewithin the colon, the compounds (especially, the gabapentin prodrug1-{[α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid) may also be more efficacious than their respective parent drugs(e.g., gabapentin or other GABA analog) in treating and/or preventingurinary incontinence. The ability of the compounds disclosed herein tobe used in sustained release oral dosage forms may also reduce thedosing frequency necessary for maintenance of a therapeuticallyeffective drug concentration in the blood.

4.5 Pharmaceutical Compositions

The pharmaceutical compositions disclosed herein comprise atherapeutically effective amount of one or more GABA analog prodrugs,preferably in purified form, together with a suitable amount of apharmaceutically acceptable vehicle, so as to provide a form for properadministration to a patient. When administered to a patient, the prodrugand pharmaceutically acceptable vehicles are preferably sterile.Suitable pharmaceutical vehicles include excipients such as starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, water, ethanol and thelike. The present pharmaceutical compositions, if desired, can alsocontain minor amounts of wetting or emulsifying agents, or pH bufferingagents. In addition, auxiliary, stabilizing, thickening, lubricating andcoloring agents may be used.

Pharmaceutical compositions may be manufactured by means of conventionalmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients orauxiliaries, which facilitate processing of compounds disclosed hereininto preparations which can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen.

The present pharmaceutical compositions can take the form of solutions,suspensions, emulsion, tablets, pills, pellets, capsules, capsulescontaining liquids, powders, sustained-release formulations,suppositories, emulsions, aerosols, sprays, suspensions, or any otherform suitable for use. In some embodiments, the pharmaceuticallyacceptable vehicle is a capsule (see e.g., Grosswald et al., U.S. Pat.No. 5,698,155). Other examples of suitable pharmaceutical vehicles havebeen described in the art (see Remington's Pharmaceutical Sciences,Philadelphia College of Pharmacy and Science, 19th Edition, 1995).Preferred pharmaceutical compositions are formulated for oral delivery,particularly for oral sustained release administration.

Pharmaceutical compositions for oral delivery may be in the form oftablets, lozenges, aqueous or oily suspensions, granules, powders,emulsions, capsules, syrups, or elixirs, for example. Orallyadministered compositions may contain one or more optional agents, forexample, sweetening agents such as fructose, aspartame or saccharin,flavoring agents such as peppermint, oil of wintergreen, or cherrycoloring agents and preserving agents, to provide a pharmaceuticallypalatable preparation. Moreover, when in tablet or pill form, thecompositions may be coated to delay disintegration and absorption in thegastrointestinal tract, thereby providing a sustained action over anextended period of time. Oral compositions can include standard vehiclessuch as mannitol, lactose, starch, magnesium stearate, sodiumsaccharine, cellulose, magnesium carbonate, etc. Such vehicles arepreferably of pharmaceutical grade.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable carriers, excipients or diluents include water,saline, alkyleneglycols (e.g., propylene glycol), polyalkylene glycols(e.g., polyethylene glycol) oils, alcohols, slightly acidic buffersbetween pH 4 and pH 6 (e.g., acetate, citrate, ascorbate at betweenabout 5 mM to about 50 mM), etc. Additionally, flavoring agents,preservatives, coloring agents, bile salts, acylcarnitines and the likemay be added.

When a GABA analog prodrug is acidic, it may be included in any of theabove-described formulations as the free acid, a pharmaceuticallyacceptable salt, a solvate or hydrate. Pharmaceutically acceptable saltssubstantially retain the activity of the free acid, may be prepared byreaction with bases, and tend to be more soluble in aqueous and otherprotic solvents than the corresponding free acid form.

The pharmaceutical compositions preferably contain no or only low levelsof lactam side products formed by intramolecular cyclization of the GABAanalog and/or GABA analog prodrug. In a preferred embodiment, thecompositions are stable to extended storage (preferably, greater thanone year) without substantial lactam formation (preferably, less thanabout 0.5% lactam by weight, more preferably, less than about 0.2%lactam by weight, most preferably, less than about 0.1% lactam byweight).

4.6 Sustained Release Oral Dosage Forms

For those methods that involve oral administration of a GABA analogprodrug to treat and/or prevent urinary incontinence, the methods can bepracticed with a number of different dosage forms, which providesustained release of the prodrug upon oral administration. Suchsustained release oral dosage forms are particularly preferred foradministering those GABA analog prodrugs that are absorbed by cellslining the large intestine, since such dosage forms are generally welladapted to deliver a prodrug to that location of the gastrointestinaltract.

In some embodiments of the invention, the dosage form comprises beadsthat on dissolution or diffusion release the prodrug over an extendedperiod of hours, preferably, over a period of at least 6 hours, morepreferably, over a period of at least 8 hours and most preferably, overa period of at least 12 hours. The prodrug-releasing beads may have acentral composition or core comprising a prodrug and pharmaceuticallyacceptable vehicles, including an optional lubricant, antioxidant andbuffer. The beads may be medical preparations with a diameter of about 1to about 2 mm. Individual beads may comprise doses of the prodrug, forexample, doses of up to about 40 mg of prodrug. The beads, in someembodiments, are formed of non-cross-linked materials to enhance theirdischarge from the gastrointestinal tract. The beads may be coated witha release rate-controlling polymer that gives a timed-release profile.

The time release beads may be manufactured into a tablet fortherapeutically effective prodrug administration. The beads can be madeinto matrix tablets by the direct compression of a plurality of beadscoated with, for example, an acrylic resin and blended with excipientssuch as hydroxypropylmethyl cellulose. The manufacture of beads has beendisclosed in the art (Lu, Int. J. Pharm. 1994, 112, 117-124;Pharmaceutical Sciences by Remington, 14^(th) ed, pp 1626-1628 (1970);Fincher, J. Pharm. Sci. 1968, 57, 1825-1835; Benedikt, U.S. Pat. No.4,083,949) as has the manufacture of tablets (Pharmaceutical Sciences,by Remington, 17^(th) Ed, Ch. 90, pp 1603-1625 (1985)).

In other embodiments, an oral sustained release pump may be used(Langer, supra; Sefton, 1987, CRC Crit Ref Biomed. Eng. 14:201; Saudeket al., 1989, N. Engl. J Med. 321:574).

In other embodiments, polymeric materials can be used (See “MedicalApplications of Controlled Release,” Langer and Wise (eds.), CRC Press,Boca Raton, Fla. (1974); “Controlled Drug Bioavailability,” Drug ProductDesign and Performance, Smolen and Ball (eds.), Wiley, New York (1984);Langer et al., 1983, J Macromol. Sci. Rev. Macromol Chem. 23:61; Levy etal., 1985, Science 228: 190; During et al., 1989, Ann. Neurol. 25:351;Howard et al., 1989, J. Neurosurg. 71:105).

In a preferred embodiment, polymeric materials are used for oralsustained release delivery. Preferred polymers include sodiumcarboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose and hydroxyethylcellulose (most preferred,hydroxypropylmethylcellulose). Other preferred cellulose ethers havebeen described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr. 1984, 5(3)1-9). Factors affecting drug release are well known to the skilledartisan and have been described in the art (Bamba et al., Int. J. Pharm.1979, 2, 307).

In other embodiments, enteric-coated preparations can be used for oralsustained release administration. Preferred coating materials includepolymers with a pH-dependent solubility (i.e., pH-controlled release),polymers with a slow or pH-dependent rate of swelling, dissolution orerosion (i.e., time-controlled release), polymers that are degraded byenzymes (i.e., enzyme-controlled release) and polymers that form firmlayers that are destroyed by an increase in pressure (i.e.,pressure-controlled release).

In yet other embodiments, drug-releasing lipid matrices can be used fororal sustained release administration. One particularly preferredexample is when solid microparticles of the prodrug are coated with athin controlled release layer of a lipid (e.g., glyceryl behenate and/orglyceryl palmitostearate) as disclosed in Farah et al., U.S. Pat. No.6,375,987 and Joachim et al., U.S. Pat. No. 6,379,700. The lipid-coatedparticles can optionally be compressed to form a tablet. Anothercontrolled release lipid-based matrix material which is suitable forsustained release oral administration comprises polyglycolizedglycerides as disclosed in Roussin et al., U.S. Pat. No. 6,171,615.

In yet other embodiments, prodrug-releasing waxes can be used for oralsustained release administration. Examples of suitable sustainedprodrug-releasing waxes are disclosed in Cain et al., U.S. Pat. No.3,402,240 (carnauba wax, candedilla wax, esparto wax and ouricury wax);Shtohryn et al., U.S. Pat. No. 4,820,523 (hydrogenated vegetable oil,bees wax, caranuba wax, paraffin, candelillia, ozokerite and mixturesthereof); and Walters, U.S. Pat. No. 4,421,736 (mixture of paraffin andcastor wax).

In still other embodiments, osmotic delivery systems are used for oralsustained release administration (Verma et al., Drug Dev. Ind. Pharm.2000, 26:695-708). In a preferred embodiment, OROS® systems made by AlzaCorporation, Mountain View, Calif. are used for oral sustained releasedelivery devices (Theeuwes et al., U.S. Pat. No. 3,845,770; Theeuwes etal. U.S. Pat. No. 3,916,899).

In yet other embodiments, a controlled-release system can be placed inproximity of the target of the prodrug of the GABA analog, thusrequiring only a fraction of the systemic dose (See, e.g., Goodson, in“Medical Applications of Controlled Release,” supra, vol. 2, pp. 115-138(1984)). Other controlled-release systems discussed in Langer, 1990,Science 249:1527-1533 may also be used.

In other embodiments, the dosage form comprises a prodrug of a GABAanalog coated on a polymer substrate. The polymer can be an erodible, ora nonerodible polymer. The coated substrate may be folded onto itself toprovide a bilayer polymer drug dosage form. For example, a prodrug of aGABA analog can be coated onto a polymer such as a polypeptide,collagen, gelatin, polyvinyl alcohol, polyorthoester, polyacetyl, or apolyorthocarbonate and the coated polymer folded onto itself to providea bilaminated dosage form. In operation, the bioerodible dosage formerodes at a controlled rate to dispense the prodrug over a sustainedrelease period. Representative biodegradable polymers comprise a memberselected from the group consisting of biodegradable poly(amides),poly(amino acids), poly(esters), poly(lactic acid), poly(glycolic acid),poly(carbohydrate), poly(orthoester), poly (orthocarbonate),poly(acetyl), poly(anhydrides), biodegradable poly(dihydropyrans), andpoly(dioxinones) which are known in the art (Rosoff, Controlled Releaseof Drugs, Chap. 2, pp. 53-95 (1989); Heller et al., U.S. Pat. No.3,811,444; Michaels, U.S. Pat. No. 3,962,414; Capozza, U.S. Pat. No.4,066,747; Schmitt, U.S. Pat. No. 4,070,347; Choi et al., U.S. Pat. No.4,079,038; Choi et al., U.S. Pat. No. 4,093,709).

In other embodiments, the dosage form comprises a prodrug loaded into apolymer that releases the prodrug by diffusion through a polymer, or byflux through pores or by rupture of a polymer matrix. The drug deliverypolymeric dosage form comprises a concentration of 10 mg to 2500 mghomogenously contained in or on a polymer. The dosage form comprises atleast one exposed surface at the beginning of dose delivery. Thenon-exposed surface, when present, is coated with a pharmaceuticallyacceptable material impermeable to the passage of a prodrug. The dosageform may be manufactured by procedures known in the art. An example ofproviding a dosage form comprises blending a pharmaceutically acceptablecarrier like polyethylene glycol, with a known dose of prodrug at anelevated temperature, (e.g., 37° C.), and adding it to a silasticmedical grade elastomer with a cross-linking agent, for example,octanoate, followed by casting in a mold. The step is repeated for eachoptional successive layer. The system is allowed to set for about 1hour, to provide the dosage form. Representative polymers formanufacturing the dosage form comprise a member selected from the groupconsisting of olefin, and vinyl polymers, addition polymers,condensation polymers, carbohydrate polymers, and silicone polymers asrepresented by polyethylene, polypropylene, polyvinyl acetate,polymethylacrylate, polyisobutylmethacrylate, poly alginate, polyamideand polysilicone. The polymers and procedures for manufacturing themhave been described in the art (Coleman et al., Polymers 1990, 31,1187-1231; Roerdink et al., Drug Carrier Systems 1989, 9, 57-10; Leonget al., Adv. Drug Delivery Rev. 1987, 1, 199-233; Roff et al., Handbookof Common Polymers 1971, CRC Press; Chien et al., U.S. Pat. No.3,992,518).

In other embodiments, the dosage from comprises a plurality of tinypills. The tiny time-release pills provide a number of individual dosesfor providing various time doses for achieving a sustained-releaseprodrug delivery profile over an extended period of time up to 24 hours.The matrix comprises a hydrophilic polymer selected from the groupconsisting of a polysaccharide, agar, agarose, natural gum, alkalialginate including sodium alginate, carrageenan, fucoidan, furcellaran,laminaran, hypnea, gum arabic, gum ghatti, gum karaya, grum tragacanth,locust bean gum, pectin, amylopectin, gelatin, and a hydrophiliccolloid. The hydrophilic matrix comprises a plurality of 4 to 50 tinypills, each tiny pill comprise a dose population of from 10 ng, 0.5 mg,1 mg, 1.2 mg, 1.4 mg, 1.6 mg, 5.0 mg, etc. The tiny pills comprise arelease rate-controlling wall of 0.001 mm up to 10 mm thickness toprovide for the timed release of prodrug. Representative wall formingmaterials include a triglyceryl ester selected from the group consistingof glyceryl tristearate, glyceryl monostearate, glyceryl dipalmitate,glyceryl laureate, glyceryl didecenoate and glyceryl tridenoate. Otherwall forming materials comprise polyvinyl acetate, phthalate,methylcellulose phthalate and microporous olefins. Procedures formanufacturing tiny pills are disclosed in Urquhart et al., U.S. Pat. No.4,434,153; Urquhart et al., U.S. Pat. No. 4,721,613; Theeuwes, U.S. Pat.No. 4,853,229; Barry, U.S. Pat. No. 2,996,431; Neville, U.S. Pat. No.3,139,383; Mehta, U.S. Pat. No. 4,752,470.

In other embodiments, the dosage form comprises an osmotic dosage form,which comprises a semipermeable wall that surrounds a therapeuticcomposition comprising the prodrug. In use within a patient, the osmoticdosage form comprising a homogenous composition, imbibes fluid throughthe semipermeable wall into the dosage form in response to theconcentration gradient across the semipermeable wall. The therapeuticcomposition in the dosage form develops osmotic pressure differentialthat causes the therapeutic composition to be administered through anexit from the dosage form over a prolonged period of time up to 24 hours(or even in some cases up to 30 hours) to provide controlled andsustained prodrug release. These delivery platforms can provide anessentially zero order delivery profile as opposed to the spikedprofiles of immediate release formulations.

In other embodiments, the dosage form comprises another osmotic dosageform comprising a wall surrounding a compartment, the wall comprising asemipermeable polymeric composition permeable to the passage of fluidand substantially impermeable to the passage of prodrug present in thecompartment, a prodrug-containing layer composition in the compartment,a hydrogel push layer composition in the compartment comprising anosmotic formulation for imbibing and absorbing fluid for expanding insize for pushing the prodrug composition layer from the dosage form, andat least one passageway in the wall for releasing the prodrugcomposition. The method delivers the prodrug by imbibing fluid throughthe semipermeable wall at a fluid imbibing rate determined by thepermeability of the semipermeable wall and the osmotic pressure acrossthe semipermeable wall causing the push layer to expand, therebydelivering the prodrug from the dosage form through the exit passagewayto a patient over a prolonged period of time (up to 24 or even 30hours). The hydrogel layer composition may comprise 10 mg to 1000 mg ofa hydrogel such as a member selected from the group consisting of apolyalkylene oxide of 1,000,000 to 8,000,000 which are selected from thegroup consisting of a polyethylene oxide of 1,000,000 weight-averagemolecular weight, a polyethylene oxide of 2,000,000 molecular weight, apolyethylene oxide of 4,000,000 molecular weight, a polyethylene oxideof 5,000,000 molecular weight, a polyethylene oxide of 7,000,000molecular weight and a polypropylene oxide of the 1,000,000 to 8,000,000weight-average molecular weight; or 10 mg to 1000 mg of an alkalicarboxymethylcellulose of 10,000 to 6,000,000 weight average molecularweight, such as sodium carboxymethylcellulose or potassiumcarboxymethylcellulose. The hydrogel expansion layer comprises 0.0 mg to350 mg, in present manufacture; 0.1 mg to 250 mg of ahydroxyalkylcellulose of 7,500 to 4,500,00 weight-average molecularweight (e.g., hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxybutylcellulose or hydroxypentylcellulose)in present manufacture; 1 mg to 50 mg of an osmagent selected from thegroup consisting of sodium chloride, potassium chloride, potassium acidphosphate, tartaric acid, citric acid, raffinose, magnesium sulfate,magnesium chloride, urea, inositol, sucrose, glucose and sorbitol; 0 to5 mg of a colorant, such as ferric oxide; 0 mg to 30 mg, in a presentmanufacture, 0.1 mg to 30 mg of a hydroxypropylalkylcellulose of 9,000to 225,000 average-number molecular weight, selected from the groupconsisting of hydroxypropylethylcellulose, hydroxypropypentylcellulose,hydroxypropylmethylcellulose, and hydropropylbutylcellulose; 0.00 to 1.5mg of an antioxidant selected from the group consisting of ascorbicacid, butylated hydroxyanisole, butylated hydroxyquinone,butylhydroxyanisole, hydroxycoumarin, butylated hydroxytoluene, cephalm,ethyl gallate, propyl gallate, octyl gallate, lauryl gallate,propyl-hydroxybenzoate, trihydroxybutylrophenone, dimethylphenol,dibutylphenol, vitamin E, lecithin and ethanolamine; and 0.0 mg to 7 mgof a lubricant selected from the group consisting of calcium stearate,magnesium stearate, zinc stearate, magnesium oleate, calcium palmitate,sodium suberate, potassium laurate, salts of fatty acids, salts ofalicyclic acids, salts of aromatic acids, stearic acid, oleic acid,palmitic acid, a mixture of a salt of a fatty, alicyclic or aromaticacid, and a fatty, alicyclic, or aromatic acid.

In the osmotic dosage forms, the semipermeable wall comprises acomposition that is permeable to the passage of fluid and impermeable tothe passage of prodrug. The wall is nontoxic and comprises a polymerselected from the group consisting of a cellulose acylate, cellulosediacylate, cellulose triacylate, cellulose acetate, cellulose diacetateand cellulose triacetate. The wall comprises 75 wt % (weight percent) to100 wt % of the cellulosic wall-forming polymer; or, the wall cancomprise additionally 0.01 wt % to 80 wt % of polyethylene glycol, or 1wt % to 25 wt % of a cellulose ether selected from the group consistingof hydroxypropylcellulose or a hydroxypropylalkycellulose such ashydroxypropylmethylcellulose. The total weight percent of all componentscomprising the wall is equal to 100 wt %. The internal compartmentcomprises the prodrug-containing composition alone or in layeredposition with an expandable hydrogel composition. The expandablehydrogel composition in the compartment increases in dimension byimbibing the fluid through the semipermeable wall, causing the hydrogelto expand and occupy space in the compartment, whereby the drugcomposition is pushed from the dosage form. The therapeutic layer andthe expandable layer act together during the operation of the dosageform for the release of prodrug to a patient over time. The dosage formcomprises a passageway in the wall that connects the exterior of thedosage form with the internal compartment. The osmotic powered dosageform can be made to deliver prodrug from the dosage form to the patientat a zero order rate of release over a period of up to about 24 hours.

The expression “passageway” as used herein comprises means and methodssuitable for the metered release of the prodrug from the compartment ofthe dosage form. The exit means comprises at least one passageway,including orifice, bore, aperture, pore, porous element, hollow fiber,capillary tube, channel, porous overlay, or porous element that providesfor the osmotic controlled release of prodrug. The passageway includes amaterial that erodes or is leached from the wall in a fluid environmentof use to produce at least one controlled-release dimensionedpassageway. Representative materials suitable for forming a passageway,or a multiplicity of passageways comprise a leachable poly(glycolic)acid or poly(lactic) acid polymer in the wall, a gelatinous filament,poly(vinyl alcohol), leach-able polysaccharides, salts, and oxides. Apore passageway, or more than one pore passageway, can be formed byleaching a leachable compound, such as sorbitol, from the wall. Thepassageway possesses controlled-release dimensions, such as round,triangular, square and elliptical, for the metered release of prodrugfrom the dosage form. The dosage form can be constructed with one ormore passageways in spaced apart relationship on a single surface or onmore than one surface of the wall. The expression “fluid environment”denotes an aqueous or biological fluid as in a human patient, includingthe gastrointestinal tract. Passageways and equipment for formingpassageways are disclosed in Theeuwes et al., U.S. Pat. No. 3,845,770;Theeuwes et al., U.S. Pat. No. 3,916,899; Saunders et al., U.S. Pat. No.4,063,064; Theeuwes et al., U.S. Pat. No. 4,088,864 and Ayer et al.,U.S. Pat. No. 4,816,263. Passageways formed by leaching are disclosed inAyer et al., U.S. Pat. No. 4,200,098 and Ayer et al., U.S. Pat. No.4,285,987.

Regardless of the specific form of sustained release oral dosage formused, the prodrug is preferably released from the dosage form over aperiod of at least about 6 hours, more preferably, over a period of atleast about 8 hours, and most preferably, over a period of at leastabout 12 hours. Further, the dosage form preferably releases from 0 to20% of the prodrug in 0 to 2 hours, from 20 to 50% of the prodrug in 2to 12 hours, from 50 to 85% of the prodrug in 3 to 20 hours and greaterthan 75% of the prodrug in 5 to 18 hours. The sustained release oraldosage form further provides a concentration of the GABA analog in theblood plasma of the patient over time, which curve has an area under thecurve (AUC) that is proportional to the dose of the prodrug of GABAanalog administered, and a maximum concentration C_(max). The C_(max) isless than 75%, and is preferably, less than 60%, of the C_(max) obtainedfrom administering an equivalent dose of the prodrug from an immediaterelease oral dosage form, and the AUC is substantially the same as theAUC obtained from administering an equivalent dose of the prodrug froman immediate release oral dosage form.

Preferably, the dosage forms of the invention are administered twice perday (more preferably, once per day).

4.7 Therapeutic Methods of Use

In some embodiments, a prodrug of a GABA analog and/or pharmaceuticalcompositions thereof is administered to a patient suffering from urinaryincontinence (whether hormonally, surgically, drug or otherwiseinduced). In other embodiments, a prodrug of a GABA analog and/orpharmaceutical compositions thereof is administered to a patient as apreventative measure against urinary incontinence (whether hormonally,surgically, drug or otherwise induced).

The present methods encompass either reducing the number and/orfrequency of urinary incontinence episodes, reducing the severity ofurinary incontinence or both. The present methods are used to treatand/or prevent urge incontinence and stress incontinence. The presentmethods may also be used to treat and/or prevent incontinence incombination with other bladder/urinary problems, for example thecombination of incontinence (i.e., involuntary loss of urine) withfrequent urination/overactive bladder, particularly in females.

The patient is a mammal, preferably a human. The patient may be eitherfemale or male, although those of skill in the art will appreciate thatthe cause of urinary incontinence can be markedly different for eithersex. (See: B. D. Weiss, “Diagnostic Evaluation of Urinary Incontinencein Geriatric Patients,” Am. Family Physician, 1998 (June) 2675-2694.)

Stress incontinence in women is generally due to two conditions:urethral hypermobility or intrinsic sphincteric deficiency (which canoccur separately or together). Urethral hypermobility is often the endresult of damage to the muscles of the pelvic floor. The weakening andstretching of the pelvic floor muscles allows the bladder to sagdownward within the abdomen. Women who have had several children throughvaginal deliveries are particularly at risk for stress incontinencebecause pregnancy and childbirth strain the muscles of the pelvic floor.Hysterectomy, which may damage the pelvic floor muscles, the sphincteritself, or the nerves that enable the sphincter muscles to contract, isa common cause of stress incontinence in women. After menopause, ortreatment before menopause with estrogen-robbing drugs, the loss ofestrogen causes the urethra to thin out so that it may not closeproperly. Intrinsic sphincteric deficiency is the other major cause ofstress incontinence in women and occurs when the sphincter muscles aredamaged or weakened.

Prostate treatments, including surgery or radiation for cancer orsurgery for benign prostatic hyperplasia, are the leading causes ofstress incontinence in men, generally by impairing the sphinctermuscles. Incontinence after these procedures is often a combination ofurge and stress and it is uncertain which type predominates.Incontinence occurs in nearly all patients for the first three to sixmonths after radical prostatectomy; after a year, however, most menhaving this procedure retain continence, although leakage can remain.Stress incontinence occurs in 1% to 5% of men after transurethralresection of the prostate (TURP), the standard treatment for severebenign prostatic hyperplasia. In both men and women, the aging processcauses a general weakening of these muscles and a decrease in bladdercapacity. High-impact exercise can also cause stress incontinence inboth genders.

In many cases, urge incontinence is due to detrusor instability, acondition in which the bladder's outer layer, the detrusor muscles,become unstable and contract inappropriately during the filling stage.Detrusor instability occurs in about 75% of men with benign prostatichyperplasia and causes frequency, urgency, and urination during thenight, although incontinence itself occurs only in very severe cases.Prostate surgical procedures, including prostatectomy and TURP, cancause detrusor instability. Incontinence rates in TURP are very low(about 1%) but they can be significant after prostatectomy. (In thelatter case, detrusor instability is usually only one of many factorsinvolved in incontinence.) Damage to the central nervous system causedby stroke, multiple sclerosis, spinal cord or disk injury, orParkinson's disease can interfere with the normal flow of nerve messagesbetween the urinary and central nervous system, resulting in detrusorhyperactivity. Infections, anxiety, and the normal aging process cancause the bladder to become overactive. Often, however, the cause ofurge incontinence is unknown. Some evidence suggests that in some casesit may be caused by ischemia (blockage of the blood vessels), the sameprocess leading to coronary artery disease.

One class of GABA analog prodrugs are those suitable for oraladministration. The promoiety or promoieties are preferably cleavedafter absorption by the gastrointestinal tract (e.g., in intestinaltissue, blood, liver or other suitable tissue of the patient) withorally administered GABA analog prodrugs. The promoiety or promoietiesmay make the prodrug a substrate for one or more transporters expressedin the large intestine (i.e., colon), and/or may let the prodrug bepassively absorbed across the mucosa for GABA analogs that are poorlyabsorbed across the gastrointestinal mucosa (e.g., gabapentin andpregabalin).

The compounds disclosed herein, particularly, the gabapentin prodrug1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, may be more efficacious than the parent drug molecule (e.g.,gabapentin or other GABA analog) in treating and/or preventing urinaryincontinence because the disclosed compounds require less time to reacha therapeutic concentration in the blood, i.e., the compounds disclosedherein have a shorter T_(max) than their parent drug counterparts whentaken orally. Without wishing to bound by theory, it is believed thatthe compounds disclosed herein, particularly the gabapentin prodrug1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, are absorbed from the gastrointestinal lumen into the blood by adifferent mechanism than that by which gabapentin and other known GABAanalogs are absorbed. For example, gabapentin is believed to be activelytransported across the gut wall by a carrier transporter localized inthe human small intestine. The gabapentin transporter is easilysaturated which means that the amount of gabapentin absorbed into theblood may not be proportional to the amount of gabapentin that isadministered orally, since once the transporter is saturated, furtherabsorption of gabapentin does not occur to any significant degree. Incomparison to gabapentin, the compounds disclosed herein, particularly,the gabapentin prodrug1-{[α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, are absorbed across the gut wall along a greater portion of thegastrointestinal tract, including the colon.

Because the compounds disclosed herein can be formulated in sustainedrelease formulations which provide for sustained release over a periodof hours into the gastrointestinal tract and particularly, releasewithin the colon, the compounds (especially, the gabapentin prodrug1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid) may also be more efficacious than their respective parent drugs(e.g., gabapentin or other GABA analog) in treating and/or preventingurinary incontinence. The ability of the compounds disclosed herein tobe used in sustained release oral dosage forms reduces the dosingfrequency necessary for maintenance of a therapeutically effective drugconcentration in the blood.

4.8 Methods of Administration and Doses

The present methods for treatment and/or prevention of urinaryincontinence require administration of a GABA analog prodrug, or apharmaceutical composition thereof, to a patient in need of suchtreatment and/or prevention. The compounds and/or pharmaceuticalcompositions thereof are preferably administered orally. The compoundsand/or pharmaceutical compositions thereof may also be administered byany other convenient route, for example, by infusion or bolus injection,by absorption through epithelial or mucocutaneous linings (e.g., oralmucosa, rectal and intestinal mucosa, etc.). Administration can besystemic or local. Various delivery systems are known, (e.g.,encapsulation in liposomes, microparticles, microcapsules, capsules,etc.) that can be used to administer a compound and/or pharmaceuticalcomposition thereof. Methods of administration include, but are notlimited to, intradermal, intramuscular, intraperitoneal, intravenous,subcutaneous, intranasal, epidural, oral, sublingual, intranasal,intracerebral, intravaginal, transdermal, rectally, by inhalation, ortopically, particularly to the ears, nose, eyes, or skin. Preferably,the compounds and/or pharmaceutical compositions thereof are deliveredvia sustained release dosage forms, more preferably via oral sustainedrelease dosage forms.

The amount of GABA analog prodrug that will be effective in thetreatment and/or prevention of urinary incontinence (whether hormonally,surgically, drug, or otherwise induced) in a patient will depend on thespecific nature of the condition, and can be determined by standardclinical techniques known in the art. In addition, in vitro or in vivoassays may optionally be employed to help identify optimal dosageranges. The amount of a prodrug administered will, of course, bedependent on, among other factors, the subject being treated, the weightof the subject, the severity of the affliction, the manner ofadministration and the judgment of the prescribing physician.

Preferably, the dosage forms are adapted to be administered to a patientno more than twice per day, more preferably, only once per day. Dosingmay be provided alone or in combination with other drugs and maycontinue as long as required for effective treatment and/or preventionof the urinary incontinence.

Suitable dosage ranges for oral administration are dependent on thepotency of the particular GABA analog drug (once cleaved from thepromoiety), but are generally about 0.1 mg to about 200 mg of drug perkilogram body weight, more preferably about 1 to about 100 mg/kg-bodywt. per day. Preferably, the GABA analog prodrug is a prodrug ofgabapentin or pregabalin. When the GABA analog is gabapentin, typicaldaily doses of the drug in adult patients are 300 mg/day to 3600 mg/dayand the dose of gabapentin prodrug may be adjusted to provide anequivalent molar quantity of gabapentin. Other GABA analogs may be morepotent than gabapentin and lower doses may be appropriate for both thecleaved drug and any prodrug (measured on an equivalent molar basis).For example, typical doses for pregabalin in the range of 100 mg/day to1200 mg/day are appropriate. Dosage ranges may be readily determined bymethods known to the skilled artisan.

4.9 Combination Therapy

In certain embodiments, GABA analog prodrugs and/or pharmaceuticalcompositions thereof can be used in combination therapy with at leastone other therapeutic agent which may be a different GABA analogprodrug. The GABA analog prodrug and/or pharmaceutical compositionthereof and the therapeutic agent can act additively or, morepreferably, synergistically. In some embodiments, a GABA analog prodrugsand/or a pharmaceutical composition thereof is administered concurrentlywith the administration of another therapeutic agent. In otherembodiments, GABA analog prodrugs and/or pharmaceutical compositionthereof is administered prior or subsequent to administration of anothertherapeutic agent.

5. EXAMPLES

The invention is further defined by reference to the following examples,which describe in detail, preparation of sustained release dosage formand methods for using GABA analog prodrugs to treat and/or preventurinary incontinence. It will be apparent to those skilled in the artthat many modifications, both to materials and methods, may be practicedwithout departing from the scope of the invention.

5.1 Example 1 Preparation of a Sustained Release Oral Dosage Form of1-{[(α-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid

A sustained release oral osmotic delivery dosage form containing thegabapentin prodrug1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid is prepared following methods described in Ayer et al., U.S. Pat.No. 5,707,663. Accordingly, 660 grams of1-{[α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and 30 grams of pharmaceutical acceptable polyethylene oxide(5,000,000 molecular weight) is added to the bowl of a fluid bedgranulator. The microencapsulation process is computerized and atomizedin cycles. The process is initiated by first fluidizing the dry drug andthe polymer powder for 3 minutes and the blended granules aremicroencapsulated with an aqueous hydroxypropylmethylcellulose solution.The polymer solution is prepared by dissolving 35 grams ofhydroxypropylmethylcellulose (11,200 molecular weight) in 400 grams ofwater. The operating conditions are as follows: spray rate of 50grams/min/nozzle (2 nozzles are used), inlet temperature 50° C.; outlettemperature 37° C. and process air flow of 400 ft³/minute. During thecoating process, the filter bag is shaken for 10 seconds after every 15seconds of solution spraying to remove any uncoated materials. A totalof 270 grams of solution is applied. After solution spraying, themicroencapsulated powder is dried in the granulator to reach a moisturecontent of 0.25%. The dried granulation is then passed through a 16 meshscreen. Next, a total of 5.3 grams of magnesium stearate is weighed out,screened through a 40 mesh screen, and blended into the granulationusing a V-blender for 2 minutes. The granulation is stored in a tightlyclosed bag with desiccants.

The osmotic displacement-push composition is then prepared as follows:first, 3.7 kg of sodium chloride, and 150 grams of red ferric oxide areseparately screened through an 8 mesh screen using a Quadro comil. Then,the screened ingredients plus 7.6 kg of pharmaceutically acceptablegrade polyethylene oxide (7,500,000 molecular weight) and 250 grams ofhydroxypropylmethylcellulose (11,200 molecular weight) are dispensedinto the bowl of a Glatt fluid bed granulator. Next, the dry powders areair suspended and mixed for 3 minutes. To prepare the binder solution420 grams of hydroxypropylmethylcellulose (11,200 molecular weight) isdissolved in 4.85 kg of water and 9.4 grams of butylated hydroxytolueneis dissolved in 60 grams of denatured ethanol. The two solutions arecombined and mixed to form the final binder solution. The conditionsmonitored during the process are as follows: solution spray rate of 400g/min (3 nozzles are used); inlet temperature 45° C.; outlet temperature24° C. and process air flow of 1,500 ft³/minute. The granulating processis computerized and automated in cycles. Each cycle contains 1.5 minutesof solution spraying followed by 10 seconds of bag shaking to remove anypossible powder deposits. A total of 4.4 kg of solution is sprayed.After solution spraying, the granulated particles are dried in thegranulator for 50 minutes at 21° C. to reach a moisture content of 0.3%.The granules are removed and sized through an 8 mesh screen. Then, 28grams of magnesium stearate, screened through a 16 mesh screen, is mixedinto the granulation using a tumbler for 3 minutes at 8 rpm.

Next, the1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid drug composition and the push composition are compressed using atablet press into bilayer cores of tablet shape as follows: first 700 mgof 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid drug composition is added to a punch and lightlyprecompressed, then 421 mg of the push composition is added and thelayers are pressed under a pressure head of 1.5 ton (3000 lbs) into a0.75″ length modified capsule contacting layered arrangement. Thecompression process is done in a humidity controlled environment. Therelative humidity during the process is 35% RH (relative humidity) orlower. The compressed cores are stored in a tightly closed bag withdesiccants.

The bilayered arrangements next are coated with a semipermeable wall.The wall-forming composition comprises 100% cellulose acetate having a˜40% acetyl content. The polymer is dissolved in 100% acetone to make a4% solid solution. The wall forming composition is sprayed at 26grams/min onto and around the bilayer cores in a tablet coater until adry weight of 90 mg/core is achieved.

Next, one 10 mil (0.254 mm) exit passageway is mechanically drilledthrough the semipermeable wall to connect the drug layer with theexterior of the dosage system. The residual solvent is removed by firstdrying for 120 hours at 50° C. and 30% relative humidity, then thesystems are dried for 2 hours at 50° C. to remove excess moisture. Thedrug dosage form produced by this process provides: ˜90 wt %1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, 4 wt % hydroxypropylmethylcellulose (11,200 molecular weight), 4wt % polyethylene oxide of 5,000,000 molecular weight and 1 wt %magnesium stearate in the drug layer. The push composition comprises63.7 wt % polyethylene oxide (7,500,000 molecular weight) 30 wt % sodiumchloride, 5 wt % hydroxypropylmethylcellulose (11,200 molecular weight)1 wt % red ferric oxide, 0.25 wt % magnesium stearate, and 0.075 wt % ofbutylated hydroxytoluene. The wall comprises 100 wt % cellulose acetatecomprising a ˜40% acetyl content. The dosage form has one passageway, 10mils (0.254 mm), and it has a1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid release rate of >20 mg/hr and a half life for drug release of >8hours in artificial gastric fluid.

5.2 Example 2 Effects of Test Compounds on Volume-Induced RhythmicBladder Voiding Contractions in Anaesthetized Rats

Female Sprague Dawley rats weighing 225-275 g are used. The animals arehoused with free access to food and water and maintained on a 12 halternating light-dark cycle at 22-24° C. for at least one week, exceptduring the experiment. The activity on the rhythmic bladder voidingcontractions is evaluated according to the method of Dray, J. Pharmacol.Methods 13:157, 1985), with some modifications as in Guarneri,Pharmacol. Res. 27: 173, 1993. Briefly, rats are anesthetized bysubcutaneous injection of 1.25 g/kg (5 ml/kg) urethane, after which theurinary bladder is catheterized via the urethra using PE 50 polyethylenetubing filled with physiological saline. The catheter is then tied inplace with a ligature around the external urethral orifice and connectedto a conventional pressure transducer. The intravesical pressure isdisplayed continuously on a chart recorder. The bladder is then filledvia the recording catheter with incremental volumes of warm (37° C.)saline until reflex bladder voiding contractions occur. After 15 min,solutions of the test compounds according to the invention areadministered by intravenous (i.v.) route into the jugular vein.

Bioactivity is assessed in individual animals (using 6-10 rats per dose)by measuring the duration of bladder quiescence (i.e., the duration oftime during which no contractions occurred) over a 60 min period.Effective doses that prevent bladder contraction for 10 minutes areevaluated by linear regression analysis to compare the potency of thetested compounds in inhibiting the bladder voiding contractions. Potencyof test compounds is compared to a known inhibitor of voidingcontractions in this assay, such as morphine, which is used as apositive control.

5.3 Example 3 Administration of1-{[(α-Isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-Cyclohexane AceticAcid to Postmenopausal Women for the Treatment of Urinary Incontinence

Twenty postmenopausal women who have been experiencing urgeincontinence, as determined by a positive diagnosis by cystometry andwho have not been treated with hormone therapy (i.e., no estrogen,progestin, tamoxifen or leuprolide therapy) over the past 2 months arerecruited to an open label clinical study of the effect ofadministration of the gabapentin prodrug on the severity of urinaryincontinence symptoms. Cystometry is performed by inserting a Frenchnonballooned urinary catheter, no. 12 to no. 14, into the bladder. Afterthe bladder empties, the plunger is removed from a bayonet-tipped 50-mLsyringe, and the tip is inserted into the end of the catheter. With thephysician holding the center of the syringe about 15 cm above theurethra, 50 mL of sterile water is poured into the open end of thesyringe and allowed to flow into the bladder. Keeping track of the totalamount of water used, the physician continues to instill water in 50-mLincrements until the patient experiences the urge to urinate. At thispoint, water instillation is continued in 25-mL increments until thepatient experiences severe urgency (“I can't hold it anymore”) orbladder contractions occur. Contractions are detected by monitoring thefluid level that appears in the syringe after several aliquots of waterhave been instilled. A rise and fall in the fluid level indicatespressure changes (i.e., contractions) within the bladder. Severe urgencyor bladder contractions at less than 300 mL of bladder volume constitutea presumptive diagnosis of urge incontinence.

The prodrug1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid (synthesized as described by Gallop et al., InternationalPublication No. WO 02/100347), formulated as osmotic sustained releasecapsules containing 700 mg drug (preparation of the sustained releasecapsules is described in Section 5.1 above), is administered twocapsules twice daily (2800 mg/day, equal to ˜1400 mg gabapentinequivalents/day) for two weeks. After completion of the drug therapy, acystometry is again performed on each patient. An increase in the amountof water by at least 20% retained by a patient's bladder before severeurgency or bladder contractions occur indicates the efficacy of thisgabapentin prodrug in treating urinary incontinence in postmenopausalwomen.

5.4 Example 4 Treatment of Urinary Incontinence in Men and Women byAdministration of1-{[(α-Isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-Cyclohexane AceticAcid via a Sustained Release Oral Dosage Form

Twenty women and twenty men who have been experiencing urinaryincontinence are recruited to an open label clinical study of the effectof administration of a gabapentin prodrug on the severity of urinaryincontinence symptoms. The prodrug1-{[α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, formulated as osmotic sustained release capsules containing 700 mgdrug (preparation of the sustained release capsules is described inSection 5.1 above), is administered in either one or two capsules perdose, each dose given twice daily (1400 mg/day or 2800 mg/day, equal to˜700 mg gabapentin equivalents/day or ˜1400 mg gabapentinequivalents/day, respectively) for two weeks. The therapeutic effect ofthe prodrug is measured by patient questionnaires, which are used todetermine, e.g., occurrence and nature of urinary incontinenceincidents, urinary frequency, nocturia, urgency or difficulty withvoiding. Effectiveness of the prodrug is measured in amelioration of anysymptom associated with urinary incontinence, as compared to a controlpatient group that is administered placebo, according to the sameregimen.

5.5 Example 5 Treatment of Urinary Incontinence in Men and Women byAdministration of1-{[(α-Isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-Cyclohexane AceticAcid

Twenty women and twenty men who have been experiencing urinaryincontinence are recruited to an open label clinical study of the effectof administration of a gabapentin prodrug on the severity of urinaryincontinence symptoms. The prodrug1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, formulated as an immediate release dosage form in 300 mg capsules,is administered in either two, three or four capsules per dose, eachdose given three times daily (1200 mg/day; 1800 mg/day; or 2400 mg/day,equal to ˜600 mg gabapentin equivalents/day; ˜900 mg gabapentinequivalents/day; or ˜1200 mg gabapentin equivalents/day, respectively)for two weeks. The therapeutic effect of the prodrug is measured bypatient questionnaires, which are used to determine, e.g., occurrenceand nature of urinary incontinence incidents, urinary frequency,nocturia, urgency, or difficulty with voiding. Effectiveness of theprodrug is measured in amelioration of any symptom associated withurinary incontinence, as compared to a control patient group that isadministered placebo, according to the same regimen.

It will be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe scope of this disclosure. Accordingly, the present embodiments areto be considered as illustrative and not restrictive, and the inventionis not to be limited to the details given herein, but may be modifiedwithin the scope and equivalents of the appended claims.

All publications and patents cited herein are incorporated by referencein their entirety.

1. A method of treating urinary incontinence in a patient in need ofsuch treatment comprising administering to the patient a therapeuticallyeffective amount of crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid.
 2. A method of treating urinary incontinence in a patient in needof such treatment comprising administering to the patient apharmaceutical composition comprising a therapeutically effective amountof crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid and a pharmaceutically acceptable cater.
 3. The method of claim 1or claim 2, wherein the patient is an adult patient and wherein thecrystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid is administered in an amount of from 300 to 3600 mg gabapentinequivalents/day.
 4. The method of claim 1 or claim 2, wherein thepatient is a female patient.
 5. The method of claim 4, wherein thefemale patient is postmenopausal.
 6. The method of claim 5, whereinmenopause is drug induced or surgically induced.
 7. The method of claim1 or claim 2, wherein the patient is a male patient.
 8. The method ofclaim 1 or claim 2, wherein the urinary incontinence is drug-induced. 9.The method of claim 1 or claim 2, wherein the crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid is administered orally.
 10. The method of claim 2, wherein thepharmaceutical composition is a sustained release oral dosage form. 11.The method of claim 10, wherein the dosage form releases crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid gradually over a period of at least about 6 hours after swallowingthe dosage form, thereby providing a therapeutic concentration ofgabapentin in the plasma of the patient.
 12. The method of claim 10,wherein the dosage form is an osmotic dosage form, a prodrug-releasingpolymer, a prodrug-releasing lipid, a prodrug-releasing wax, tinytimed-release pills or prodrug releasing beads.
 13. The method of claim1 or claim 2, wherein the urinary incontinence is characterized bysymptoms of urge incontinence.
 14. The method of claim 1 or claim 2,wherein the urinary incontinence is characterized by symptoms of stressincontinence.